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Lombardy has represented the Italian and European epicenter of the coronavirus disease 2019 (COVID-19) pandemic. Although most clinical efforts within hospitals were diverted towards the care of virally infected patients, therapies for patients with cancer, including radiotherapy (RT), have continued. During both the first and second pandemic waves, several national and regional organizations provided Italian and Lombardian RT departments with detailed guidelines aimed at ensuring safe treatments during the pandemic. The spread of infection among patients and personnel was limited by adopting strict measures, including triage procedures, interpersonal distance, and adequate implementation of personal protective equipment (PPE). Screening procedures addressed to both the healthcare workforce and patients, such as periodic nasopharyngeal swabs, have allowed the early identification of asymptomatic or pauci-symptomatic COVID-19 cases, thus reducing the spread of the infection. Prevention of infection was deemed of paramount importance to protect both patients and personnel and to ensure the availability of a minimum number of staff members to maintain clinical activity. The choice of treating COVID-19–positive patients has represented a matter of debate, and the risk of oncologic progression has been weighted against the risk of infection of personnel and other patients. Such risk was minimized by creating dedicated paths, reserving time slots, applying intensified cleaning procedures, and supplying personnel and staff with appropriate PPE. Remote working of research staff, medical physicists, and, in some cases, radiation oncologists has prevented overcrowding of shared spaces, reducing infection spread.

The purpose of this study was to evaluate the effect of 3D visualization applied to laparoscopic appendectomy (LA) performed by young surgeons (YS). We considered both operative features and clinical outcomes, aiming to highlight the benefits that this technology could bring to novice surgeons and their laparoscopic training. All the surgical procedures were performed by residents who had performed less than 20 appendectomies prior to the beginning of the study under the supervision of an expert surgeon. At the time of enrolment patients were randomized into two arms: Experimental arm (EA): laparoscopic appendectomy performed with laparoscopic 3D vision technology. Control arm (CA): laparoscopic appendectomy performed with the "standard" 2D technology. The primary endpoint was to find any statistically significant difference in operative time between the two arms. Differences in conversion rate, intra-operative complications, post-operative complications and surgeons’ operative comfort were considered as secondary endpoints. We randomized 135 patients into the two study arms. The two groups were homogeneous for demographic characteristics, BMI and ASA scores. The characteristics of clinical presentation and anatomical position showed no significant difference. The operative time was longer in the CA (57.5 vs. 49.6 min, p = 0.048, 95% CI). In the subgroup of complicated appendicitis, this trend toward inferior operative time was confirmed without reaching statistical significance (2D = 60 min, 3D = 49.5 min, p = 0.082 95% CI). No intra-operative complications were observed in either group. The conversion rate was 5.6% (4 patients) in the 2D group and 4.6% (3 patients) in 3D group. The utilization of 3D laparoscopy was associated with reduction in operative time without influencing other parameters, in particular without altering the safety profile of the procedure.

Targeted therapy improves outcomes in BRAF V600-mutant metastatic melanoma with active brain metastases. We present the case of a patient with rapid brain disease progression upon temporary targeted therapy discontinuation and unusual rapid disease response upon treatment resumption. This report presents a 78-year-old woman with metastatic BRAF V600E positive melanoma (bladder and brain localizations). The patient started first-line dabrafenib and trametinib with good tolerability and evidence of complete response (CR). After 8 months of maintained CR, the patient took a drug holiday for 14 days. Brain MRI performed after treatment pause showed extensive disease progression, whereas extracranial staging was negative. The patient was asymptomatic: she restarted targeted therapy and underwent evaluation for whole-brain radiotherapy. Brain computed tomography scan and subsequent MRI performed to plan radiotherapy showed brain CR after only 10 days of targeted therapy resumption. The patient continued treatment, and radiotherapy indication was withheld. Repeated brain MRI confirmed maintained CR. Treatment with dabrafenib and trametinib is ongoing with excellent tolerability. Rapid intracranial progression is a well-known finding after discontinuation of combined targeted therapy in the case of extracranial progressive disease. This is the first report of documented disease progression upon temporary treatment discontinuation for reasons other than toxicity, with an unusual response after retreatment. Caution should be used in tailoring treatment during targeted therapy, allowing pauses for reasons other than toxicity. Strict adherence to treatment is paramount to guarantee disease control.

Background Italy experienced one of the world’s severest COVID-19 outbreak, with Lombardy being the most afflicted region. However, the imposed safety measures allowed to flatten the epidemic curve and hence to ease the restrictions and inaugurate, on the 4th of May 2020, the Italian phase (P) 2 of the pandemic. The present survey study, endorsed by CODRAL and AIRO-L, aimed to assess how radiotherapy (RT) departments in Lombardy have dealt with the recovery. Materials and methods A questionnaire dealing with the management of pandemic was developed online and sent to all CODRAL Directors on the 10th of June 2020. Answers were collected in full anonymity one week after. Results All the 33 contacted RT facilities (100%) responded to the survey. Despite the scale of the pandemic, during P1 14 (42.4%) centres managed to safely continue the activity (≤ 10% reduction). During P2, 10 (30.3%) centres fully recovered and 14 (42.4%) reported an increase. Nonetheless, 6 (18.2%) declared no changes and, interestingly, 3 (9.1%) reduced activities. Overall, 21 centres (63.6%) reported suspected or positive cases within healthcare workforce since the beginning of the pandemic. Staff units were quarantined in 19 (57.6%) and 6 (18.2%) centres throughout P1 and P2, respectively. In the two phases, about two thirds centres registered positive or suspected cases amongst patients. Conclusion The study revealed a particular attention to anti-contagion measures and a return to normal or even higher clinical workload in most RT centres in Lombardy, necessary to carry out current and previously deferred treatments. Electronic supplementary material The online version of this article (10.1007/s12032-020-01434-1) contains supplementary material, which is available to authorized users.

Introduction: Several efforts are being implemented at the European level to measure provision of up-to-date radiation treatments across the continent. Methods: A snapshot survey involving all radiation oncology centers within Lombardy, Italy, was performed in 2012 and repeated in 2014 and 2016, in cooperation with regional governmental officers. Centers were asked to provide detailed information concerning all individual patients being treated on the index day, and to report data on available local resources. Results: We observed an increase in the number of centers and of megavoltage units (MVU) (from 76 to 87, i.e., 8.7 MVU per million inhabitants in 2016). Mean number of MVU per center was 2.5. Average age of MVU increased from 5.3 to 7.5 years and patients on the waiting list also increased. Conformal 3D radiotherapy (RT) treatments decreased from 56% to 42% and were progressively replaced by intensity-modulated RT treatments (from 39% to 49%). Waiting times were overall satisfactory. Radiation oncologists treated on average 152 and radiation therapists 100 RT courses per year. Average reimbursement per course was €4,879 (range €2,476–€8,014). Conclusions: The methodology of snapshot survey proved feasible and provided valuable information about radiation oncology provision and accessibility in Lombardy.

The purpose of this study was to evaluate the effect of 3D visualization applied to laparoscopic appendectomy (LA) performed by young surgeons (YS). We considered both operative features and clinical outcomes, aiming to highlight the benefits that this technology could bring to novice surgeons and their laparoscopic training.All the surgical procedures were performed by residents who had performed less than 20 appendectomies prior to the beginning of the study under the supervision of an expert surgeon. At the time of enrolment patients were randomized into two arms: Experimental arm (EA): laparoscopic appendectomy performed with laparoscopic 3D vision technology. Control arm (CA): laparoscopic appendectomy performed with the "standard" 2D technology. The primary endpoint was to find any statistically significant difference in operative time between the two arms. Differences in conversion rate, intra-operative complications, post-operative complications and surgeons' operative comfort were considered as secondary endpoints.We randomized 135 patients into the two study arms. The two groups were homogeneous for demographic characteristics, BMI and ASA scores. The characteristics of clinical presentation and anatomical position showed no significant difference. The operative time was longer in the CA (57.5 vs. 49.6 min, p = 0.048, 95% CI). In the subgroup of complicated appendicitis, this trend toward inferior operative time was confirmed without reaching statistical significance (2D = 60 min, 3D = 49.5 min, p = 0.082 95% CI). No intra-operative complications were observed in either group. The conversion rate was 5.6% (4 patients) in the 2D group and 4.6% (3 patients) in 3D group.The utilization of 3D laparoscopy was associated with reduction in operative time without influencing other parameters, in particular without altering the safety profile of the procedure.

The aim of the present study was to characterize the population dynamics of the fiddler crab Uca maracoani in a mangrove area of the Formoso River, state of Pernambuco, northeast of Brazil. Samplings were performed monthly (April 2009 to March 2010) by one collector during 30 min at the low tide. A total of 1198 individuals (753 males and 445 females) were sampled, and all of them had measured the carapace width (CW), the major cheliped propodus length of males (CPL) and the abdomen width of females (AW). Sex and the ovigerous condition were recorded. Mean size of males (CW) (22.9 ± 6.61 mm) was significantly greater than that of females (20.2 ± 5.2 mm). Morphological sexual maturity estimated for males and females was 15.8 and 13.8 mm of CW, respectively. In the size-frequency distribution of both sexes, the population showed two cohorts, consisting of a juvenile group and an adult group. Sex ratio was diverted in favor of males (1.6:1.0), and males were more frequent in larger size classes. The reproductive period was based on the low rate of ovigerous females found throughout the year, occurring from June to August 2009. The recruitment was continuous throughout the year, but more intense during spring. Results of the present study are the first recorded from the state of Pernambuco and not only enabled a better comprehension of the population biology of U. maracoani along its latitudinal distribution, but also allowed to observe the population stability in the Formoso River mangrove.

Progesterone (P4) is a natural steroid hormone excreted by humans and animals. Noncomplete degradation in treatment plants result in levels in the ng/L range in surface waters. Very little is known of the effects on fish at such concentrations. Here we determine the global expression profile in the brain and ovary of female zebrafish exposed for 14 days to 3.5 33 and 306 ng/L P4 to elucidate molecular effects. For validation selected transcripts were determined by RT qPCR. In the brain 54 and 255 transcripts were altered at 3.5 and 306 ng/L respectively. Genes related to circadian rhythm (nr1d2b per1b) cell cycle and reproduction (cdc20 ccnb1) were down regulated. In the ovary transcriptional changes occurred in 200 84 and 196 genes at 3.5 33 and 306 ng/L respectively. The genes belong to different pathways including cardiac hypertrophy cell cycle and its regulation. P4 slightly influenced oocyte maturation as revealed by histology of the ovaries. In the liver vtg1 was down regulated at all concentrations and VTG protein at 306 ng/L in the blood. The data show molecular effects and the modes of action of P4 at environmental concentrations. Ultimately they may translate to adverse effects on reproduction.

Purpose: To compare volumetric modulated arc therapy with flattening filter free (FFF) and flattening filter (FF) beams in patients with hepatic metastases subject to hypofractionated radiotherapy (RT). Methods: A planning study on 13 virtual lesions of increasing volume was performed. Two single arc plans were optimized with the RapidArc technique using either FFF or FF beams. A second planning study was performed on ten patients treated for liver metastases to validate conclusions. In all cases, a dose of 75 Gy in 3 fractions was prescribed to the planning target volume (PTV) and plans were evaluated in terms of coverage, homogeneity, conformity, mean dose to healthy liver and to healthy tissue. For each parameter, results were expressed in relative terms as the percentage ratio between FFF and FF data. Results: In terms of PTV coverage, conformity index favored FFF for targets of intermediate size while FF resulted more suitable for small ( 300 cm3) targets. Plans optimized with FFF beams resulted in increased sparing of healthy tissue in ≈85% of cases. Despite the qualitative results, no statistically significant differences were found between FFF and FF results. Plans optimized with un-flattened beams resulted in higher average MU/Gy than plans with FF beams. A remarkable and significant difference was observed in the beam-on time (BOT) needed to deliver plans. The BOT for FF plans was 8.2 ± 1.0 min; for FFF plans BOT was 2.2 ± 0.2 min. Conclusions: RapidArc plans optimized using FFF were dosimetrically equivalent to those optimized using FF beams, showing the feasibility of SBRT treatments with FFF beams. Some improvement in healthy tissue sparing was observed when using the FFF modality due to the different beam's profile. The main advantage was a considerable reduction of beam-on time, relevant for SBRT techniques.

Purpose We report the medium-term clinical outcome of hypofractionated stereotactic body radiotherapy (SBRT) in a series of patients with either a solitary metastasis or oligometastases from different tumors to abdominal lymph nodes. Methods and Materials Between January 2006 and June 2009, 19 patients with unresectable nodal metastases in the abdominal retroperitoneal region were treated with SBRT. Of the patients, 11 had a solitary nodal metastasis and 8 had a dominant nodal lesion as part of oligometastatic disease, defined as up to five metastases. The dose prescription was 45 Gy to the clinical target volume in six fractions. The prescription had to be downscaled by 10% to 20% in 6 of 19 cases to keep within dose/volume constraints. The first 11 patients were treated with three-dimensional conformal techniques and the last 8 by volumetric intensity-modulated arc therapy. Median follow-up was 1 year. Results Of 19 patients, 2 had a local progression at the site of SBRT; both also showed concomitant tumor growth at distant sites. The actuarial rate of freedom from local progression was 77.8% ± 13.9% at both 12 and 24 months. Eleven patients showed progressive local and/or distant disease at follow-up. The 12- and 24-month progression-free survival rates were 29.5% ± 13.4% and 19.7% ± 12.0%, respectively. The number of metastases (solitary vs. nonsolitary oligometastases) emerged as the only significant variable affecting progression-free survival ( p Conclusions Stereotactic body radiotherapy for metastases to abdominal lymph nodes was shown to be feasible with good clinical results in terms of medium-term local control and toxicity rates. Even if most patients eventually show progressive disease at other sites, local control achieved by SBRT may be potentially significant for preserving quality of life and delaying further chemotherapy.

This paper aims to study the morphological and gonadal maturity of the swimming crab Callinectes danae in the Santa Cruz Channel, Brazil. Crabs of both sexes were measured at carapace width (CW), carapace length (CL), abdomen width (AW), length of the right chelipod (LRC), and dissected to visualize the gonads. The gonadal maturity was estimated based on the frequency of mature individuals per class of CW, and the determination of morphological maturity was based on the relationship between the structures LRC versus CW for males and AW versus CW for females. The sizes that 50% of females reached gonadal and morphological maturity were 62.5 and 59.5 mm CW respectively. In turn, the sizes that 50% of males reached gonadal and morphological maturity were 74.5 and 70.5 mm CW respectively. In the analysis of dispersion of points in relation to AW versus CW, it could be observed that juvenile females showed positive allometry and adult females showed negative allometry, indicating a higher growth rate during the juvenile phase, related to the need of expanding the abdomen for egg incubation at the adult phase. In the relation LRC versus CW, it was observed that both juvenile and adult males showed positive allometry, but changes in the degree of allometry were evident between the two phases. The exceeding growth of the chelipod of males may be related to the reproductive process, including courtship and agonistic interactions with other males.

This study was carried out in order to provide basic information on the population ecology of the crab Sesarma rectum in the Ariquindá River mangrove, Tamandaré, State of Pernambuco, Brazil. The population was analysed with regard to the following aspects, in particular: the size-class frequency distribution of carapace width (CW), mean body size (CW) of males and females, morphological sexual maturity, sex-ratio, reproductive period, and recruitment. Samples were collected monthly from April 2008 through to March 2009; the crabs were collected manually, with a capture effort by one person for 30 minutes, during low tide. The specimens obtained were measured for CW, length of the propodus of males, and abdomen width of females; and the sex and ovigerous condition were noted. Altogether, we obtained 511 specimens (132 juvenile and 137 adult males, and 171 juvenile and 71 adult females, of which 32 were ovigerous). The median CW of males (16.15 mm) was significantly larger than that of females (13.82 mm) (P P > 0.05). The sex-ratio by size-class showed an anomalous pattern, with a greater abundance of males in the larger size-classes. The reproductive period was continuous and the highest frequency of ovigerous females was recorded in the spring and summer. The major pulse of recruitment occurred during autumn and winter, which is related to greater reproductive activity during the warmer months of the year.

To report early clinical experience in stereotactic body radiation therapy (SBRT) delivered using volumetric intensity modulated arc therapy with RapidArc (RA) in patients with primary or metastatic tumours at abdominal sites.Thirty-seven consecutive patients were treated using RA. Of these, 16 had primary or metastatic liver tumours, nine had pancreatic cancer and 12 a nodal metastasis in the retro-peritoneum. Dose prescription varied from 45 to 75 Gy to the Clinical Target Volume in 3 to 6 fractions. The median follow-up was 12 months (6-22). Early local control and toxicity were investigated and reported.Planning objectives on target volumes and organs at risk were met in most cases. Delivery time ranged from 2.8 ± 0.3 to 9.2 ± 2.4 minutes and pre-treatment plan verification resulted in a Gamma Agreement Index from 95.3 ± 3.8 to 98.3 ± 1.7%. At the time of analysis, local control (freedom from progression) at six months, was assessable in 24 of 37 patients and was achieved in 19 patients with a crude rate of 79.2%. Seven patients experienced treatment-related toxicity. Three patients experienced a mild and transient G1 enteritis and two showed a transient G1 liver damage. Two had late toxicity: one developed chronic enteritis causing G1 diarrhoea and G1 abdominal pain and one suffered at three months a G3 gastric bleeding. No patients experienced G4 acute toxicity.SBRT for abdominal targets delivered by means of RA resulted to be feasible with good early clinical results in terms of local control rate and acute toxicity profile. RA allowed to achieve required target coverage as well as to keep within normal tissue dose/volume constraints.

The purpose of this study was to quantify the relationship between treatment time and dose uncertainty due to intrafraction organ motion in prostate cancer radiotherapy (RT). Ten consecutive patients with prostate cancer treated by radical RT by volumetric modulated arc therapy (RapidArc) were considered. For each patient, pre‐ and post‐treatment cone beam computed tomography (CBCT) was performed in 10 fractions. The prostate, rectum and bladder were contoured on each CBCT. The change in organ position, volume and dosimetric uncertainty induced by organ motion were evaluated. Interval time between the two CBCTs ranged between 4 and 16 min (mean 7.3±0.7 min). Treatment with intrafraction prostate motion > 3 mm and > 5 mm were 24% and 5%, respectively. Regarding change in centroid position and volume, a poor time correlation was found for target and rectum, while a constant increase was obtained for bladder. The agreement index was highly correlated to time (r=−0.89 for bladder, r=−0.95 for rectum, and r=−0.84 for prostate). In terms of difference in dose volume histogram between pre‐ and post‐CBCT, the dose uncertainties for the targets and rectum amplified with the increasing time. The increasing intrafraction dose uncertainty with time requires the use of an RT technique with minimization of treatment time to improve confidence in planning dose distribution. PACS number: 87.55.tm

Aims In 2013, a survey was conducted to analyze the available resources and their use in the radiation treatment of patients with malignancies of the head and neck region in Lombardy, on behalf of the Lombardy group of the Italian Association of Radiation Oncology. Methods A questionnaire was sent to 26 of 34 radiotherapy centers active in the region. Two centers were excluded because they did not treat head and neck cancers (Besta Neurological Institute and Cyberknife center), 4 had started their activity in 2013 or late 2012, and 2 satellite centers had their results included in the main center's response. Items investigated included number of patients with head and neck cancer treated in 2012, general technical issues, and integration with surgery and chemotherapy. Results Twenty-four questionnaires were returned (92% response rate). There was a good consistency on the use of radiotherapy in different settings, whereas integration with chemotherapy showed more heterogeneous data. Treatment techniques were 3D conformal radiotherapy or intensity-modulated radiotherapy with image-guided radiotherapy in most cases and a low rate of treatment-related death was observed. Conclusions This survey provides important data on the use of radiotherapy resources for patients with head and neck cancer in Lombardy. The data offer the opportunity to further investigate issues that could better standardize head and neck cancer treatment and allocate resources across the region.

The aim of this longitudinal study is to present data from 76 female patients treated with bisphosphonates (BPs) for postmenopausal osteoporosis and referred to the Unit of Oral Diagnosis and Day Surgery of the University of Milano for diagnosis and treatment. All patients received a thorough oral examination. The diagnosis of osteonecrosis of the jaw bone (ONJ) was made from radiographic and clinical findings. 9% of individuals had BRONJ at first visit. Patients with dental or periodontal abscess were significantly more likely to develop BRONJ (OR: 2.9, 95% CI 0.5–15.9). Patients with osteoporosis receiving BPs may develop BRONJ, especially in the presence of an active infectious process in the mouth. Clinicians should carefully follow up on individuals receiving bisphosphonates therapy to avoid the occurrence of osteonecrotic lesions.

We aimed to collect and analyze clinical data from a cohort of 76 female patients treated with biphosphonates (BP) for postmenopausal osteoporosis and referred to the Unit of Oral Diagnosis and Day Surgery for diagnosis and treatment. Methods: Each patient received a throughout oral, dental and periodontal examina- tion. Relevant clinical data regarding the BP treatment and comorbidities, oral findings and dental treatment plan, past and present dental therapies were recorded. All individuals had been recalled every three months for clinical examination, oral hygiene instructions and professional scaling; when needed periodontal, restorative and dento- alveolar surgical treatments were provided with strict protocols, according to the international guidelines. Results: Over the last 4 years period, 76 consecutive patients aged 51 to 91 yrs (mean=68,6 yrs) and treated with BP for postmenopausal osteoporosis were referred (alendronate n= 47, clodronate n=16, risedronate n=10, ibandronate n=3 - mean treatment time= 190 wks); at the referral time osteonecrosis of the jaws (ONJ) has been identified in 7 patients (stage I n=3, stage II n=4 - mandibula n=6, both jaws n=1). The duration of BP therapy in ONJ patients ranged from 24 to 432 wks. The triggering events for ONJ were identified as dentoalveolar surgery (n=2), local trauma from dentures (n=3) and periodontal infection (n=2). In the ONJ group, 5 patients were never smokers and 2 had systemic comorbidities. Treatment and control of the ONJ cases was obtained with repeated antibacterial treatments and in 4 patients with surgical debridement of the affected areas. Closure of the exposure and complete remission has been obtained in 4 cases. At present none of the non-ONJ patients submitted to invasive dental treatments developed ONJ signs and/or symptoms. Conclusions: ONJ could be a harmful side effect of BP treatments in postmenopausal osteoporosis patients as well as non-oncologic patients. Oral prevention and appro- priate protocols for invasive oral surgery could minimize the risk of ONJ. Relevance: BP related ONJ prevalence in non-oncologic patients could be further reduced with focused management of oral health and diseases.

Parameter estimation for rainfall-runoff models in ungauged basins is a challenging task that is receiving significant attention by the scientific community. In fact, many practical applications suffer from problems induced by data scarcity, given that hydrological observations are often sparse or unavailable. This study focuses on regional calibration for a generic rainfall-runoff model. The maximum likelihood function in the spectral domain proposed by Whittle [40] is approximated in the time domain by maximising the fit of selected statistics of the river flow process, with the aim to propose a calibration procedure that can be applied at regional scale. Accordingly, the statistics above are related to the dominant climate and catchment characteristics, through regional regression relationships. The proposed technique is applied to the case study of 4 catchments located in central Italy, which are treated as ungauged and are located in a region where detailed hydrological, as well as geomorphologic and climatic information, is available. The results obtained with the regional calibration are compared with those provided by a classical least squares calibration in the time domain. The outcomes of the analysis confirm the potential of the proposed methodology and show that regional information can be very effective for setting up hydrological models.

Recent studies highlight that geostatistical interpolation, which has been originally developed for the spatial interpolation of point data, can be effectively applied to the problem of regionalization of hydrometric information. This study compares two innovative geostatistical approaches for the prediction of low-flows in ungauged basins. The first one, named Physiographic-Space Based Interpolation (PSBI), performs the spatial interpolation of the desired streamflow index (e.g., annual streamflow, low-flow index, flood quantile, etc.) in the space of catchment descriptors. The second technique, named Topological kriging or Top-Kriging, predicts the variable of interest along river networks taking both the area and nested nature of catchments into account. PSBI and Top-Kriging are applied for the regionalization of Q355 (i.e., the streamflow that is equalled or exceeded 355 days in a year, on average) over a broad geographical region in central Italy, which contains 51 gauged catchments. Both techniques are cross-validated through a leave-one-out procedure at all available gauges and applied to a subregion to produce a continuous estimation of Q355 along the river network extracted from a 90 m DEM. The results of the study show that Top-Kriging and PSBI present complementary features and have comparable performances (Nash-Sutcliffe efficiencies in cross-validation of 0.89 and 0.83, respectively). Both techniques provide plausible and accurate predictions of Q355 in ungauged basins and represent promising opportunities for regionalization of low-flows.

Low-flow estimation is of great importance to assess the availability of water resources. This study investigates the applicability of physiographical space-based interpolation techniques for the prediction of low-flow indices in ungauged basins (basins for which discharge observations are sparse or unavailable). The study considers 51 catchments located in a wide region of central Italy, for which several geomorphological and climatic descriptors are available. The analysis applies both deterministic and geostatistical techniques for interpolating low-flow indices in the physiographical space. A jack-knife cross-validation procedure is applied in order to quantify the accuracy of each technique when it is applied to ungauged basins. The results of the study show that physiographical space-based interpolation is a viable approach for estimating low-flow indices in ungauged basins and geostatistical techniques outperform deterministic techniques.

Purpose: Conflicting opinions exist in literature concerning the management of oral surgery in patients on oral anticoagulants, since no consensus on perioperative protocols or guidelines on therapy modification or withdrawal are available. The aim of the present study was to evaluate bleeding complications associated to oral surgery performed in patients on oral anticoagulants without therapy modification or withdrawal but following a standardized comprehensive perioperative management protocol.Methods: 255 patients (mean age 67.8±9.5, range 27-89 years on anticoagulant therapy with warfarin and in need for oral surgery underwent a thorough general and oral clinical evaluation in order to assess thromboembolic and bleeding risk. Subjects who on the morning of surgery had PT-INR values ≤ 5.5 were included in the study. An atraumatic surgical technique was carried out and all patients received postoperative careful instructions.Results: 334 interventions were carried out on 255 patients. According to thromboembolic risk, 41 patients were classified as low risk, 115 moderate risk and 99 high risk. According to bleeding risk, 127 patients (189 interventions) were classified as low and 128 (145 interventions) as high risk. Preoperatory PT-INR were comprised between 1.3 and 5.4 (average 2.7±1.2). Five cases (1.96%) of bleeding complication were observed in patients with moderate to high thromboembolic and bleeding risk.Conclusions and Relevance: A comprehensive perioperative management protocol for oral surgery in patients on oral anticoagulants including (i) thromboembolic and bleeding risk assessment, (ii) an atraumatic surgical technique and (iii) postoperative careful instructions, can lead to safe and successful results with minimal complications. BACKGROUND: Matrix metalloproteinases (MMPs) play pivotal roles in tumor progression. MMP-13 (collagenase-3) digests collagen and other extracellular components. MATERIALS AND METHODS: Reverse transcriptase-polymerase chain reaction (RT-PCR), immunohistochemistry and zymograph were used to study the roles of MMP-13 during the neoplastic process of oral squamous cell carcinoma (OSCC). RESULTS: Increase of MMP-13 mRNA and protein expression in OSCC cell lines relative to cultivated normal oral keratinocytes was found. MMP-13 mRNA expression in OSCC was significantly higher than in non-cancerous match tissue (NCMT) in 36 tissue pairs. Esophageal squamous cell carcinoma also exhibited high MMP-13 mRNA expression. The percentage of OSCC exhibiting strong MMP-13 immunoreactivity was significantly higher than pre-invasive lesion and NCMT. Treatment with >5 μm epigallocatechin-3-gallate (EGCG) to OEC-M1 cells suppressed the expression and activity of MMP-13. CONCLUSION: MMP-13 could be a potential tumor marker for OSCC. The effects of EGCG in tumor inhibition may act partially through the modulation of MMP-13.

Purpose To assess the feasibility, acute toxicity, clinical improvement, local control and survival for spinal metastatic patients re-irradiated using volumetric-modulated-arc-radiotherapy (VMAT). Methods and materials Between February 2009 and November 2010, 31 patients were treated. Surgery was performed in six before re-irradiation. The clinical target volume (CTV) was defined as the whole vertebrae with recurrence excluding the central section of spinal canal. Planning target volume was defined as CTV+0–5mm in the three directions. Dose was prescribed in order to have biological equivalent dose to the spinal cord from the two courses lower than 120Gy 2 to 1cc of the volume. Clinical improvement, toxicity and recurrence were evaluated. All patients had back pain before treatment and 15 (48%) neurological deficit. Results Clinical remission of pain was obtained in 29 patients (93%). Neurological improvement was observed in 73% of patients. No acute or late toxicities were recorded. No recurrence occurred. Median survival was 10months (range 6–24). At the last follow-up 19 patients (61%) were alive and 12 (39%) dead from systemic disease progression. The 1 and 2year survival were 55% and 35%, respectively. Conclusion In patients with spinal metastases recurrence re-irradiation with VMAT is feasible and provides clinical benefit in most patients.

Purpose/Objective(s): To assess the safety of high-dose stereotactic body radiation therapy (SBRT) with volumetric modulated arc therapy (VMAT) technique for the treatment of patients with unresectable liver metastases from solid tumors, with special regard on liver function. Materials/Methods: Patients with 1 to 3 unresectable liver metastases with maximum individual tumor diameters less than 6 cm, a Karnofsky Performance Status of at least 70 and life expectancy more than 6 months were enrolled and treated by SBRT on a phase II clinical trial. Dose prescription to mean clinical target volume (CTV) was 75 Gy in 3 consecutive days, with planning target volume (PTV) covered by at least the isodose of 67%, and where possible, this limit on PTV was increased up to 95% of the prescription. When the dose constraints for normal tissues could not be fulfilled, dose reduction up to 30% was allowed. SBRT was administered using VMAT technique by RapidArc, with a flattening filterfree photon beam 10 MV (FFF) and maximum dose rate of 2400 MU/min. Results: Between February 2010 and August 2011, 57 patients with 77 lesions were enrolled in this trial. Among them, 21% had extrahepatic disease at the time of SBRT. Primary tumor sites were colon in 24, breast in 19, bilio-pancreatic in 6, uterus in 5, and others in the remaining 17. Seventyfour (74%) of patients had 1 lesion, 19% and 7% of patients had 2 and 3 lesions, respectively. Sixty-three lesions (82%) were treated with a full dose of 75 Gy. Dose reduction was provided in only 14 lesions to respect the dose constraints. Mean beam-on time was 2.9 1.5 min (range, 1.9-6.2 min). None of the patients experienced grade 3 or higher acute toxicity. Grade 2 acute toxicity, mainly gastrointestinal, occurred in 7 patients (14%). No radiation-induced liver disease (RILD) was detected. Given the short length of follow-up, no data on late toxicity are currently available. Conclusions: Findings suggest that SBRT for unresectable liver metastases is associated with a low incidence of acute toxicity, and can be considered as a safe and noninvasive therapeutic option in this setting.

To describe feasibility, tolerability and clinical outcomes of stereotactic body radiation therapy (SBRT) in the treatment of adrenal metastases in 34 consecutive cancer patients.Between March 2004 and July 2010, a total of 34 consecutive patients, accounting for 36 adrenal metastatic lesions, were treated with SBRT. SBRT treatments were delivered by a Linac Varian 600 with microMLC (3DLine, Elekta, Stockholm, Sweden) and a Linac ELEKTA Precise (Elekta). All 34 patients were clinically and radiologically evaluated during and after completion of SBRT. Following outcomes were taken into account: best clinical response at any time, local control, time to systemic progression, time to local progression, overall survival and toxicity. Survival was estimated by the Kaplan-Meier method and factor potentially affecting outcomes were analyzed with Cox regression analysis.Total RT doses ranged from 20 Gy in 4 fractions to 45 Gy in 18 fractions (median dose: 32 Gy; median number of fractions: 4). All doses were prescribed to the 95% isodose line. No cases of Grade ≥ 3 toxicity were recorded. At a median follow-up time of 41 months (range, 12-75) 22 patients were alive. Three of 28 lesions (11%) showed complete response, 13/28 (46%) partial response, 10/28 (36%) stable disease and 2/28 (7%) progressed in the treated area. Local failure was observed in 13 cases. Actuarial local control rates at one and two years were 66% and 32%, respectively. Median time to local progression was 19 months. Median survival was 22 months.SBRT in adrenal gland metastasis is feasible without significant acute and late toxicities, with a good rate of local control. New SBRT fractionation schemes and the possibility to combine new systemic approaches should be investigated in order to further increase local control and reduce systemic disease progression.

The purpose of this study was to evaluate the possibility of dose distribution optimization for total marrow irradiation (TMI) employing volumetric‐modulated arc therapy (VMAT) with RapidArc (RA) technology setting isocenter's positions and jaw's apertures according to patient's anatomical features. Plans for five patients were generated with the RA engine (PROIII): eight arcs were distributed along four isocenters and simultaneously optimized with collimator set to 90°. Two models were investigated for geometrical settings of arcs: (1) in the “symmetric” model, isocenters were equispaced and field apertures were set the same for all arcs to uniformly cover the entire target length; (2) in the “anatomy driven” model, both field sizes and isocenter positions were optimized in order to minimize the target volume near the field edges (i.e., to maximize the freedom of motion of MLC leaves inside the field aperture (for example, avoiding arcs with ribs and iliac wings in the same BEV)). All body bones from the cranium to mid of the femurs were defined as PTV; the maximum length achieved in this study was 130 cm. Twelve (12) Gy in 2 Gy/fractions were prescribed in order to obtain the covering of 85% of the PTV by 100% of the prescribed dose. For all organs at risk (including brain, optical structures, oral and neck structures, lungs, heart, liver, kidneys, spleen, bowels, bladder, rectum, genitals), planning strategy aimed to maximize sparing according to ALARA principles, looking to reach a mean dose lower than 6 Gy (i.e., 50% of the prescribed dose). Mean MU/fraction resulted 3184±354 and 2939±264 for the two strategies, corresponding to a reduction of 7% (range −2% to 13%) for (1) and (2). Target homogeneity, defined as D2%−D98% was 18% better for (2). Mean dose to the healthy tissue, defined as body minus PTV, had 10% better reduction with (2). The isocenter's position and the jaw's apertures are significant parameters in the optimization of the TMI with RA technique, giving the medical physicist a crucial role in driving the optimization and thus obtaining the best plan. A clinical protocol started in our department in October 2010. PACS numbers: 87.55.de, 87.55.dk, 87.56.nk, 87.57.uq

Background To report about early clinical experience in radiation treatment of head and neck cancer of different sites and histology by volumetric modulated arcs with the RapidArc technology. Methods During 2009, 45 patients were treated at Istituto Clinico Humanitas with RapidArc (28 males and 17 females, median age 65 years). Of these, 78% received concomitant chemotherapy. Thirty-six patients were treated as exclusive curative intent (group A), three as postoperative curative intent (group B) and six with sinonasal tumours (group C). Dose prescription was at Planning Target Volumes (PTV) with simultaneous integrated boost: 54.45Gy and 69.96Gy in 33 fractions (group A); 54.45Gy and 66Gy in 33 fractions (group B) and 55Gy in 25 fractions (group C). Results Concerning planning optimization strategies and constraints, as per PTV coverage, for all groups, D98% > 95% and V95% > 99%. As regards organs at risk, all planning objectives were respected, and this was correlated with observed acute toxicity rates. Only 28% of patients experienced G3 mucositis, 14% G3 dermitis 44% had G2 dysphagia. Nobody required feeding tubes to be placed during treatment. Acute toxicity is also related to chemotherapy. Two patients interrupted the course of radiotherapy because of a quick worsening of general clinical condition. Conclusions These preliminary results stated that volumetric modulated arc therapy in locally advanced head and neck cancers is feasible and effective, with acceptable toxicities.

To compare advanced treatment techniques with photons and protons as a stereotactic body radiation therapy (SBRT) for adrenal glands metastases.Planning computer tomographic (CT) scans of 10 patients were selected. A total dose of 45 Gy in 7.5 Gy fractions was prescribed. Organs at risk (OAR) were liver and kidneys. Dose-volume metrics were defined to quantify quality of plans assessing target coverage and sparing of organs at risk. Plans for RapidArc, intensity-modulated radiotherapy (IMRT), dynamic conformal arcs, 3D conformal static fields, and intensity modulated protons were compared. The main planning objective for the clinical target volume (CTV) was to cover 100% of the volume with 95% (V(95%) = 100%) and to keep the maximum dose below 107% of the prescribed dose (V(107%) = 0%). Planning objective for planning target volume (PTV) was V(95%)80%. For kidneys, the general planning objective was V(15Gy)35% and for liver V(15Gy)(liver volume-700 cm(3)).All techniques achieved the minimum and maximum dose objective for CTV and PTV, D(5-95%) ranged from 1 Gy (protons) to 1.6 Gy (conformal static fields) on CTV. Maximal organ at risk sparing was achieved by protons. RapidArc presented the second lowest dose bath (V(10Gy) and integral dose) after protons and the best conformality together with IMRT.Stereotactic body radiation therapy (SBRT) to adrenal glands metastases is achievable with several advanced techniques with either photons or protons. The intensity modulated approaches using either static fields, dynamic arcs or protons are superior to the other conformal solutions. For their simplicity, IMRT or RapidArc should be considered as the first option radiation treatment for those patients not eligible for proton treatment.

The fiddler crab Uca (Minuca) victoriana von Hagen, 1987 has been reported, until recently, only from the type locality at Vito´ria, State of Espı´rito Santo, Brazil. We report here, for the first time, the occurrence of U. (M.) victoriana in estuaries of the States of Bahia and Pernambuco, north-eastern Brazil, extending its distribution; as well as some aspects of its population biology. For the population study, four sites were defined in mangroves of the Mamucabas and Ariquinda´ Rivers, Pernambuco, on different types of substrate, and sampled monthly during spring low tide from April 2008 through to March 2009. A total of 41 specimens were obtained in June 2008 in the Arinquinda´ River, of which 25 were males, 16 nonovigerous females and 1 ovigerous female. In the Mamucabas River, 772 crabs were collected over the year, including 472 males, 300 non-ovigerous females and 2 ovigerous females. In both areas, the U. (M.) victoriana population showed a unimodal size –frequency distribution, with males and females (ovigerous and non-ovigerous) similar in size (7.46 + 1.60 mm for males and 7.09 + 1.45 mm for females; t ¼ 20.744; P . 0.05). The overall sex-ratio (1:1.57) differed significantly from the expected 1:1 proportion1 (x2 ¼ 38.32; P , 0.05). Study of material deposited in Brazilian carcinological collections revealed several misidentified specimens, especially as U. (M.) rapax and U. (M.) burgersi. Some morphological characters to distinguish among these species are presented.

During the past years our group focused on the development and optimization of an industrial production process for manufacturing of lots of the non-MHC restricted human citotoxic cell line TALL-104 for cell therapy applications. To assess the behaviour of the frozen cell bags during the storage period and after long distance shipping, we performed stability experiments and shipping tests on three different TALL-104 lots produced at our facility. Cells were assayed for biological activity using a cytotoxic assay. The stability study allowed us to set the expiration date for TALL-104 lots at two years after manufacturing.

The latest developments in Lewy Body Dementia (DLB) raise some controversies on clinical features, neuroimaging and therapy. The aim of our study is to determine clinical, neuropsychological, neuroimaging and EEG profile of DLB through retrospective and prospective data of 102 patients.data were collected with an analytical form that was developed by an expertise of neurologists.DLB represented 4.8% of the dementia population, with no sex difference. Family history of dementia was common (24.5%), while familiarity for parkinsonism was rare (4.9%). Cognitive disturbances were the predominant clinical presentation at onset (49%), followed by behavioral symptoms (29.4%) and parkinsonism (21.6%). Clinical features at consultation were: memory disturbances (almost all cases), symmetrical (68.6%) or asymmetrical (18.6%) parkinsonism, cognitive fluctuations (49%), visuospatial deficits (53.9%), and visual hallucinations (44.1%). Autonomic signs were present in a third of the cases, while sleep disorders were present in 44.1%. Some clinical response to antiparkinsonian drugs was evident in half of the cases. MRI, SPET, EEG and Neuropsychiatric Inventory data were available in a subgroup of patients.Most of our data were in accordance with the previous literature. However, some data underline the relationship between DLB, Alzheimer's and Parkinson's disease.

Introduction The radiation oncology process along with its unique therapeutic properties is also potentially dangerous for the patient, and thus it should be delivered under a systematic risk control. To this aim incident reporting and analysis are not sufficient for assuring patient safety and proactive risk assessment should also be implemented. The paper accounts for some methodological solutions, lessons learned and opportunities for improvement, starting from the systematic application of the failure mode effects and criticality analysis (FMECA) technique to the radiotherapy process of an Italian hospital. Materials and methods The analysis, performed by a working group made of experts of the radiotherapy unit, was organised into the following steps: (1) complete and detailed analysis of the process (integration definition for function modelling); (2) identification of possible failure modes (FM) of the process, representing sources of adverse events for the patient; (3) qualitative risk assessment of FMs, aimed at identifying priorities of intervention; (4) identification and planning of corrective actions. Results Organisational and procedural corrective measures were implemented; a set of safety indexes for the process was integrated within the traditional quality assurance indicators measured by the unit. A strong commitment of all the professionals involved was observed and the study revealed to be a powerful “tool” for dissemination of patient safety culture. Conclusion The feasibility of FMECA in fostering radiotherapy safety was proven; nevertheless, some lessons learned as well as weaknesses of current practices in risk management open to future research for the integration of retrospective methods (e.g. incident reporting or root cause analysis) and risk assessment.

Objective: To assess whether different patterns of regional gray matter loss in patients with mild cognitive impairment (MCI) are associated with different risks of conversion to Alzheimer disease (AD), using MRI and voxel-based morphometry (VBM). Methods: The authors recruited 22 patients with MCI, 22 patients with probable AD, and 20 healthy subjects (HS). T1 volumes from each subject were postprocessed according to an optimized VBM protocol. All patients were clinically followed up (mean [SD] time = 28.7 [5.7] months), and patients with MCI were reclassified into two groups (converters and nonconverters to AD). Results: When comparing patients with AD to HS, widespread areas of reduced gray matter density were found predominantly in temporal, frontal, and parietal lobes and in the insula. Comparing MCI converters and nonconverters with HS, the converters showed more widespread areas of reduced gray matter density than nonconverters, with a pattern of abnormalities similar to that seen in patients with AD. Conversely, when comparing the same groups with patients with AD, MCI nonconverters showed a pattern of gray matter density similar to that of HS. Areas of decreased gray matter density were also found in MCI converters compared with nonconverters. Conclusions: Different patterns of gray matter density distribution in patients with mild cognitive impairment may be associated to different rates of conversion to Alzheimer disease.

Aims and Background Androgen ablation therapy in conjunction with radiotherapy-neoadjuvant and adjuvant – has consistently been shown to be associated with improved biochemical and local control, whereas controversy still remains as regards its benefit in terms of overall survival. The objective of this study is to determine the impact of androgen ablation in combination to 3D-conformal radiotherapy on late treatment-related toxicity. Methods 236 patients were treated with 3D-conformal radiotherapy to a total dose ranging from 70 and 78.6 Gy. Fifty-six patients did not receive any form of androgen ablation whereas 176 were given at least 3 months of neoadjuvant androgen ablation. Of these, 64 stayed on androgen ablation for a median time of 6 months post-radiotherapy. Acute toxicity was evaluated weekly during the course of treatment. Late toxicity was assessed at 3-months intervals during the follow-up. Toxicity was scored according to the RTOG criteria. Results The median follow-up was 24.6 months (range, 12-62). The incidence of late genitourinary toxicity was: 3% G2, 3.5% G3, 0.5% G4. The incidence of late gastrointestinal toxicity was: 12% G2, 2% G3, 1% G4. No association was observed between the use of androgen ablation and late treatment-related toxicity. High-risk patients who continued on androgen ablation long-term were not found to have an increased risk of developing late toxicity with respect to those who never had any form of androgen ablation or those only treated neoadjuvantly. Conclusions In our experience, the use of androgen ablation does not impact on late toxicity following high dose 3D-conformal radiotherapy for prostate cancer.

The launch on the market of an increasing number of antibody-based drugs had, as consequence, the parallel development of recipient cell lines, serum free media and bioreactors for production of big quantities of these molecules. Most of the destiny of a biopharmaceutical drug is played during the process development, a step that appears in all biotech projects but very often is not properly carried out with the hurry to go to production. This loss of accuracy at early stages of the development can cause problems in reliability of lots during manufacturing with potential risks of stopping/delaying the project in advanced phases of development. We describe here a strategy for the process development of monoclonal antibodies for clinical studies.

Many pharmacologically active substances are used every year in the world for human and animal health care. Some are excreted unmetabolised or as active metabolites, escaping degradation in sewage treatment plants, and enter the environment, affecting surface waters and groundwaters (Halling-Sorensen et al. 1998). Drugs used in aquaculture are emitted directly into surface waters. Improper disposal of expired medication can contribute to this pollution. Since pharmaceuticals may have long half-lives in the environment, they can accumulate, reaching biologically active levels (Daughton and Ternes 1999). The environmental persistence of several commonly used medicinal drugs, such as erythromycin, cyclophosphamide, naproxen, sulfamethoxazole, sulfasalazine, and quinolones is longer than one year, and clofibric acid is estimated to persist for several years (Zuccato et al. 2001). This massive use of medicinal products can therefore potentially contaminate the environment, with risks for wildlife. Furthermore, resistant bacteria may be selected by persistent and accumulating antibiotics, which might be one source of the growing number of antibiotic-resistant pathogens in human medicine (Kumpel et al. 2001). Data are scant on the amounts of the different active substances emitted into wastewater, surface water or soil. Recent investigations indicated not only that several drugs are detectable in the effluent from sewage treatment plants, but also that several are not degraded and can reach ng 1−11 and μg l−1 concentrations in rivers and drinking water (Ollers et al. 2001; Zuccato et al. 2000).

Until recently information on pharmaceuticals emitted in the environment was scanty. In the last two decades, pharmaceuticals such as clofibrate, analgesics, antibiotics and antineoplastics have been found in the effluent of sewage treatment plants (STP) (Halling-Sorensen et al.1998; Kummerer 2001). Some of these compounds were not readily biodegradable and were also detectable in surface water and groundwater (Oilers et al. 2001; Sacher et al. 2001). Several pharmaceuticals have been detected in the µg l−1 range in wastewaters throughout Europe, and some have been measured at ng l−1 concentrations in rivers and drinking water (Halling-Sorensen et al. 1998; Kummerer 2001; Ollers et al. 2001; Sacher et al. 2001; Zuccato et al. 2000).