GPU-accelerated Monte Carlo simulation of electron and photon interactions for radiotherapy applications.

Objective. The Monte Carlo simulation software is a valuable tool in radiation therapy, in particular to achieve the needed accuracy in the dose evaluation for the treatment plans optimisation. The current challenge in this field is the time reduction to open the way to many clinical applications for which the computational time is an issue. In this manuscript we present an innovative GPU-accelerated Monte Carlo software for dose valuation in electron and photon based radiotherapy, developed as an update of the FRED (Fast paRticle thErapy Dose evaluator) software.Approach. The code transports particles through a 3D voxel grid, while scoring their energy deposition along their trajectory. The models of electromagnetic interactions in the energy region between 1 MeV-1 GeV available in literature have been implemented to efficiently run on GPUs, allowing to combine a fast tracking while keeping high accuracy in dose assessment. The FRED software has been bench-marked against state-of-art full MC (FLUKA, GEANT4) in the realm of two different radiotherapy applications: Intra-Operative Radio Therapy and Very High Electron Energy radiotherapy applications.Results. The single pencil beam dose-depth profiles in water as well as the dose map computed on non-homogeneous phantom agree with full-MCs at 2% level, observing a gain in processing time from 200 to 5000.Significance. Such performance allows for computing a plan with electron beams in few minutes with an accuracy of ∼%, demonstrating the FRED potential to be adopted for fast plan re-calculation in photon or electron radiotherapy applications.

[The involvement of pulmonary interstitial tissue in multisystemic lupus erythematosus: interdisciplinarity and role of the pneumologists]. / Il coinvolgimento dell'interstizio polmonare nel lupus eritematoso multisistemico: interdisciplinarietà e ruolo dello pneumologo.

The Author remarks the interstitial lung involvement in systemic lupus erythematosus. This secondary respiratory manifestation is infrequent as well as the consequent pulmonary hypertension making it possible to miss or delay the diagnosis. Therefore the interdisciplinary evaluation of the multisystemic disease lupus erythematosus needs. In this context the role of the pneumologists is relevant for the global treatment of the patients with LES in particular as concerns the early detection of the clinical and functional respiratory symptoms as well as the appropriate treatment plan within their specialistic competence.

[The longsurvivors for non-small cell lung cancer: remarks on the present and in perspective]. / Le lungosopravvivenze nel carcinoma broncogeno non-microcitoma: riflessioni criticamente "obbligate" sul presente e in prospettiva.

The Authors fully share cricitisms voiced in international literature to NSCLC longsurvivors, in particular those remarkes related to advanced disease patients following various anti-tumor treatments ( mostly multimodal). To this point, even the NCCN version 3.2014 guidelines prove inadequate as they mostly focus on longsurvivors post-NSCLC early stage surgical resection. Although AIOM Working Group's recommendations for follow-up seem to be more adequate, still they lack depth with respect to advanced-stage bronchogenic carcinoma. The Authors quote a number of case report related to advanced disease longsurvivors, and draws his attention on the peculiar role of pneumologists in the follow-up for such patients: in particular, as regards respiratory pathologies prior or subsequent to different anti-tumor treatments (i.e., BPCO, interstitial lung diseases, pulmonary thromboembolism, etc.).

[On adjuvant therapy after limited resections for NSCLC Stage IA in patients with high risk of recurrence: waiting for the announced 8th Edition 2017 of TNM Staging System]. / Sulla terapia adiuvante dopo resezioni limitate per NSCLC Stadio IA in pazienti ad alto rischio di recidiva: in attesa della annunciata 8a edizione 2017 del TNM Staging System.

The adjuvant therapy in NSCLC Stage IA still remains a controversial issue even in the interdisciplinary decision making after limited resections of the neoplasm as an alternative to lobectomy. The Authors accept from literature that this mainly concerns specific sub-group of patients, the istopathological post-resection diagnosis of whom highlights linfovascular o perineural as well as visceral pleura invasion. There is confidence that the presently depersonalizing rigidity in the guidelines implementation is overcome in the presence of clear istological signs of invasion. As a consequence the interdisciplinary team should reasonably consider as correct the adjuvant treatment.

[Toward the overcoming of controversies about adjuvant chemotherapy in patients radically resected for NSCLC stage IA]. / Verso il superamento delle controversie per la chemioterapia adiuvante in pazienti radicalmente operati per NSCLC stadio IA

The Author remarks the dispute about the adjuvant chemotherapy in patients with completely resected NSCLC stage IA. The tendency to overcoming all these disputes on the basis of relevant data published in the pneumological literature, is taking shape. The most active role in this field of research is played by the pathologists as well as by thoracic surgeons in the interdisciplinary perspective concerning the new changed "scenario" after the 7th Edition 2009 of TNM Staging System.

[Revisiting iatrogenic damage in pneumology past and current implications compared]. / Le attuali implicazioni pneumologiche del danno polmonare iatrogeno alla luce di una rivisitazione rispetto al passato.

Current features of iatrogenic damage by pneumological practice are taken into account and compared with those traced in the past by Daddi and colleagues. The Authors stress the major chances occurred over time and moreover they emphasize the correlated implications that took place with prevention, therapies, informed consent and defensive medicine. Especially in oncological as well as non-oncological field the more relevant iatrogenic damages are represented by the pulmonary interstitial disease and pulmonary thromboembolism. However, from the revisiting is emerged that at present time are strongly increased the possibility and the means for preventing the onset of iatrogenic damage as well as the possibility of reducing the size of lesions consequent upon the pharmacological, surgical and radiotherapeutics treatments.

[Occult mediastinal node involvement in non-small cell lung cancer after negative uptake on PET/CT: ripples through staging and therapy. Case report and critical review]. / Linfonodi mediastinici "occulti" nel NCCLC: ripercussioni della falsa negatività PET/TC sulla stadiazione e sulla terapia. Caso clinico e rassegna critica.

A 78-years old man, heavy smoker, with a persistent and hacking cough, was diagnosed with an adenocarcinoma of upper lobe of left lung. Clinical stage was defined as cT2N0M0 also on the basis of a negative (18)FDG-PET/TC. After lobectomy, pathological stage resulted, on the contrary, pT2N2M0. Because the considerable incidence of preoperative false negative uptakes of PET/TC for involvement of mediastinal lymph nodes, this case report is highlighted as emblematic, particularly in relation to post-operative treatment of early stage NSCLC.

Bilateral suprascapular nerve entrapment by glenoid labral cysts associated with rotator cuff damage and posterior instability in an amateur weightlifter.

Suprascapular nerve entrapment is a common condition in athletes. The entrapment is most frequently due to a "glenoid labral cyst" produced by joint fluid extrusion in consequence of labral degenerative changes. The bilaterality of the entrapment and the association with rotator cuff pathology are a rare evidence. We present the case of a 38-year-old amateur weightlifter with an history of left shoulder chronic posterior pain and progressive external rotation weakness, and with an acute right shoulder pain and weakness. Magnetic resonance imaging showed a bilateral glenoid labral cyst in association with partial tear of the supraspinatus tendon, atrophy of the infraspinatus muscle and type 2 SLAP lesion at the left shoulder and subacromial impingement syndrome (due to acromio-clavicular osteophyte), mild atrophy of the infraspinatus muscle and type 1-2 SLAP lesion at the right side.

Mucoid metaplastic-degeneration of anterior cruciate ligament.

AIM: Mucoid degeneration of the anterior cruciate ligament (ACL) is a pathological state not yet well morphologically defined, involving people without history of knee instability or significant trauma, and causing important pain. The aim of this study was to define the histopathological and radiographic features of this pathological condition. METHODS: Analysis of 1 215 knee magnetic resonance (MR) examinations found 64 cases (5.3%) of ACL mucoid metaplastic-degeneration (MMD), subsequently all subjects underwent surgical and arthroscopic validation. MR examinations have been performed using a dedicate system provided with a permanent magnet of 0.18 T and with a dedicate coil of 12 cm of field of view (FOV) or an high field instrument with 1.5 T. Radiological criteria to define ACL MMD were based essentially on increased signal intensity in T2W sequences and in STIR ones, as in T1W scans the ligament showed an intermediate signal. RESULTS: ACL MMD was diagnosed in 36 males and 28 females, with a mean age of 44 years. ''Segmentary MMD'' was found in 11 subjects (17.2%) commonly affecting the postero-lateral bundle of the ligament without femoral or tibial spongious mucoid intrusion. ''Total MMD'' (involving the entire ligament and accompanied with femoral or tibial intrusion) was found in 53 subjects (82.8%). CONCLUSION: The comparison between histopathological and MR findings suggests that the commonly called ACL mucoid degeneration (ACL MD) should be better defined as mucoid metaplastic degeneration (MMD).

Inhibition of thromboxane biosynthesis by triflusal in type 2 diabetes mellitus.

Triflusal is an antiplatelet drug related to aspirin, with different pharmacological properties and a lower haemorrhagic risk. We aimed at comparing their effects on platelet and endothelial activation in type 2 diabetes mellitus (T2DM). In a randomized, double-blind, parallel group study, we compared the effects of three daily regimens (300, 600, and 900 mg) of triflusal, and aspirin (100mg/day) on urinary 11-dehydro-thromboxane (TX)B(2), index of in vivo platelet activation, ex vivo platelet function using the analyzer PFA-100, plasma von Willebrand factor (vWF), P-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and serum nitrite and nitrate (NO(2)(-)+NO(3)(-)) in 60 T2DM patients. Triflusal induced a dose-dependent reduction in 11-dehydro-TXB(2) and a prolongation of closure time in the presence of collagen plus epinephrine (Coll/Epi-CT). The effects of the highest triflusal dose were not different from those of aspirin. The closure time in the presence of collagen plus ADP (Coll/ADP-CT), ICAM-1, VCAM-1, and NO(2)(-)+NO(3)(-) were not modified either by triflusal or aspirin. Plasma P-selectin and vWF were reduced by triflusal but not by aspirin. In T2DM triflusal causes a profound inhibition of platelet TXA(2) biosynthesis in vivo, acting on different targets involved in the platelet-endothelial cell interactions.

Role of platelet surface receptor abnormalities in the bleeding and thrombotic diathesis of uremic patients on hemodialysis and peritoneal dialysis.

BACKGROUND: Patients with chronic renal failure suffer from bleeding diathesis and a tendency to accelerated atherosclerosis. Altered platelet function plays a well defined role in the hemorrhagic complications of these patients and has a probable impact on atherothrombotic disease in uremia. In this study we investigated the expression of platelet surface receptors, the glycoprotein GPIb (receptor for von Willebrand Factor(vWF) and GPIIb/IIIa (receptor for fibrinogen) in patient with chronic renal failure in pre-dialysis status, under hemodialysis and peritoneal dialysis treatment, in order to assess the impact of the abnormal receptorial status of uremic platelets on the clinical manifestations of hemostatic alterations in uremic patients. METHODS: Thirty-seven normal healthy subjects (controls = Group A), 18 patients with mild chronic renal failure (creatinine = 1.8 +/- 0.5 mg% - Group B), 15 patients with advanced renal failure (creatinine = 5.4 +/- 2. 1 mg% - Group C), 18 hemodialysis patients (Group D) and 11 peritoneal dialysis patients (Group E) were included in the study. The expression of platelet surface receptors GPIb and GPIIb/IIIa was investigated with monoclonal antibodies CD42 and CD41 (Immunotech, Marseille, France) and a FACScan flowcytometer (Becton-Dickinson, USA). RESULTS: Mean values of GPIb glycoprotein (mean flow +/- SD) were: group A = 48.14 +/- 9.31; group B = 40.48 +/- 8.18 (p < 0.005); group C = 34.05 +/- 7.55 (p < 0.0005) versus group A; p = 0.025 versus group B); group D = 34.51 +/- 7.22 (p < 0.0005 versus group A; p = 0.025 group B and p = ns versus group C); group E = 26.34 +/- 4.06 (p < 0.0005 versus group A, p < 0.0005 versus group B, p < 0.005 versus groups C and D). Mean values of glycoprotein GPIIb/IIIa were: group A = 375.32 +/- 90.58; group B = 398.48 +/- 54.26 (p = ns); group C = 426.86 +/- 52.78 (p < 0.025 versus group A; p = ns versus group B); group D = 425.17 +/- 75.03 (p < 0.025 versus group A; p = ns versus groups B and C); group E = 336.39 +/- 43.26 (p = ns versus group A; p < 0.005 versus group B, p < 0.0005 versus group C and p < 0.001 versus group D). CONCLUSIONS: Our data confirm the receptorial defect of glycoprotein GPIb (the receptor for vWF) on the surface of uremic platelets: a negative correlation between serum creatinine and the expression of glycoprotein GPIb was found. The defect was not corrected by hemodialysis and/or peritoneal dialysis. Hemodialysis and peritoneal dialysis have a different impact on the expression of GPIIb/IIIa glycoprotein (the receptor for vWF): peritoneal dialysis seems to have a more favourable effect by restoring normal values of the expression of this membrane integrine. Theoretically the data could be correlated to the better biocompatibility of the peritoneal dialysis and to more favorable clinical behaviour in terms of accelerated atherosclerosis and athero-thrombotic complications in the uremic patients with end stage renal disease. Finally the abnormalities of platelet surface receptors may play a main role in the hemostatic alterations of uremic patients.

Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-small-cell lung cancer.

PURPOSE: New effective chemotherapy is needed to improve the outcome of patients with advanced non-small-cell lung cancer (NSCLC). Paclitaxel administered as a single agent or in combination with cisplatin has been shown to be a potentially new useful agent for the treatment of NSCLC. PATIENTS AND METHODS: Between January 1995 and April 1996, 414 patients with stage IIIB or IV NSCLC were randomized to received either a control arm of high-dose cisplatin (100 mg/m(2)) or a combination of paclitaxel (175 mg/m(2), 3-hour infusion) and cisplatin (80 mg/m(2)) every 21 days. RESULTS: Compared with the cisplatin-only arm, there was a 9% improvement (95% confidence interval, 0% to 19%) in overall response rate for the paclitaxel/cisplatin arm (17% v 26%, respectively; P=.028). Median time to progression was 2.7 and 4.1 months in the control and paclitaxel/cisplatin arm, respectively (P=.026). The study, however, failed to show a significant improvement in median survival for the paclitaxel/cisplatin arm (8.6 months in the control arm v 8.1 months in the paclitaxel/cisplatin arm, P=.862). There was more hematotoxicity, peripheral neuropathy, and arthralgia/myalgia on the paclitaxel/cisplatin arm, whereas the high-dose cisplatin arm produced more ototoxicity, nausea, vomiting, and nephrotoxicity. Quality of life (QOL) was similar overall between the two arms. CONCLUSION: This large randomized phase III trial failed to show a significant improvement in survival for the paclitaxel/cisplatin combination compared with high-dose cisplatin in patients with advanced NSCLC. However, the paclitaxel/cisplatin combination did produce a better clinical response, resulting in an increased time to progression while providing a similar QOL.

Ambamustine in the second-line treatment of patients with small-cell lung cancer: a phase II Fonicap study.

Despite a high probability of response to first-line chemotherapy, most patients with small-cell lung cancer (SCLC) will eventually have progression of their disease because of the development of resistant disease. Second-line testing of new drugs is an accepted research strategy in SCLC. In this context, the Italian Lung Cancer Task Force (FONICAP) has tested a new synthetic bifunctional alkylating agent, Ambamustine, with preliminary evidence of activity in other solid tumors. Patients with measurable SCLC, progressive after one first-line chemotherapy regimen (either "sensitive" or "refractory"), were eligible for the study. Ambamustine was administered at the dose of 2 mg/kg as a 1-hour intravenous infusion on day 1 every 21 days. The dose was to be increased to 3 mg/kg if no grade IV toxicity and complete hematologic recovery had occurred by day 22. Sample size was calculated according to a two-stage optimal Simon's design. Seventeen patients were entered into the study. Twelve patients were refractory to prior chemotherapy; 12 had extensive disease; the median age was 64 years (range: 46-75 years) and the median performance status was 1. Among 13 patients who received more than one cycle, 9 patients could increase Ambamustine dose from 2 to 3 mg/kg. No objective response was observed: one patient obtained a 50% regression of the primary tumor with contemporary disease progression in the liver and was qualified as having progressive disease. The treatment was well tolerated: grade IV leukopenia occurred in only 1 patient; grade III anemia occurred in 17.6%, grade III leukopenia in 11.8%, and grade III thrombocytopenia in 23.5%. Nonhematologic toxicity was minimal. Ambamustine, at the dose and schedule used in this study, is well tolerated in pretreated patients with SCLC but has no significant antitumor activity in this unfavorable group of patients.

Treatment of inoperable non-small cell lung carcinoma stage IIIb and IV with cisplatin, epidoxorubicin, vindesine and lonidamine: a phase II study.

AIMS AND BACKGROUND: The polychemotherapeutic regimen PEV (cisplatin, epidoxorubicin and vindesine) + lonidamine proved to be valid in terms of activity and efficacy in the treatment of patients with advanced, previously untreated non-small cell lung carcinoma. The goal of the study was to verify whether a different dose of lonidamine, together with an increase in cisplatin and epidoxorubicin compared to the standard regimen, is able to improve the activity and efficacy of PEV without increasing toxicity. PATIENTS AND METHODS: Thirty-one patients were treated with cisplatin (80 mg/m2/i.v.), epidoxorubicin (70 mg/m2/i.v.) and vindesine (3 mg/m2/i.v.) every 28 days for 6 courses in combination with lonidamine (600 mg/day on days 1 and 2 of each course followed by 450 mg/day until progression of disease or intolerance). All the patients were monitored for clinical response, median duration of response and survival and for toxicity. RESULTS: The clinical response in the 29 assessable patients was: 41.4% partial remission, 48.3% stable disease, and 10.3% progression of disease. The median duration of response was 8.5 months (range, 4-26+) and median survival was 12 months (range, 4-26+). Survival was above the median in 15 stage IIIb patients, and 2 patients were long survivors at 26+ months. The toxicity of PEV + lonidamine was mild; there were no toxic deaths nor acute toxicity of grade 4 according to the WHO scoring system. CONCLUSIONS: Our polychemotherapeutic regimen proved to be valid in terms of activity and efficacy, and a further dose increase in single chemotherapeutic agents as well as lonidamine could therefore be justified.

The role of vindesine and lonidamine in the treatment of elderly patients with advanced non-small cell lung cancer: a phase III randomized FONICAP trial. Italian Lung Cancer Task Force.

AIMS: To evaluate the efficacy and treatment compliance in elderly patients with advanced non-small cell lung cancer (NSCLC) of two chemotherapeutic agents with mild toxicity, 153 previously untreated patients aged over 70 years were randomized to receive lonidamine (450 mg daily p.o. until progression), vindesine (3 mg/m2/daily i.v. weekly for 4 weeks and then every 2 weeks until progression), the combination of the two drugs at the same dose and schedule, or supportive therapy only in a four-arm factorial randomized trial. METHODS: 126 patients were included in the final analysis. Their median age was 75 years. Forty percent had stage IV disease and 60% stage III. Most patients were males (85%) and the majority had squamous histology (68%). RESULTS: Among 104 patients evaluable for response there were only 3 PRs (1/30 in the lonidamine arm and 2/33 in the lonidamine + vindesine arm). Overall, 8.7% and 9.5% of the patients, respectively, progressed or died early, before response evaluation; another 9.4% refused treatment continuation because of poor compliance with the study protocol. Eighty-five patients were fully evaluable for toxicity, which was generally mild. Leukopenia grade 1-3 was found in less than 30% of patients treated with vindesine or vindesine + lonidamine. The most common complaints associated with lonidamine treatment were myalgia (70% of patients), fatigue (55% and 83% of patients treated with lonidamine or lonidamine + vindesine, respectively) and testicular pain in nearly 40% of cases. The overall median survival was 170 days, with no significant impact on survival of either lonidamine or vindesine. CONCLUSIONS: The low response rate and survival together with the poor treatment compliance, even in the presence of mild toxicity, do not support the usefulness of these "gentle" chemotherapies in elderly NSCLC patients. The standard management of advanced NSCLC in elderly patients remains to be defined. Specifically designed studies to address this issue are warranted.

Cisplatin-vindesine-mitomycin (MVP) vs cisplatin-ifosfamide-vinorelbine (PIN) vs carboplatin-vinorelbine (CaN) in patients with advanced non-small-cell lung cancer (NSCLC): a FONICAP randomized phase II study. Italian Lung Cancer Task Force (FONICAP).

In the present multicentre randomized phase II trial, the activity and toxicity of three platinum-based combination regimens for the treatment of advanced non-small-cell lung cancer (NSCLC) were evaluated. The three regimens were: MVP (mitomycin-C 6 mg m(-2) on day 1, vindesine 3 mg m(-2) on days 1 and 15, and cisplatin 80 mg m(-2) on day 1 every 28 days), PIN (cisplatin 80 mg m(-2) day 1, ifosfamide 3 g m(-2) day 1 and vinorelbine 25 mg m(-2) day 1 and 8 every 21 days) and CaN (carboplatin 350 mg m(-2) day 1 and vinorelbine 25 mg m(-2) days 1 and 8 every 28 days). A total of 140 chemotherapy-naive patients entered the study; 49 patients were treated with MVP, 48 with PIN and 43 with CaN. Sixty-seven per cent of the patients had stage IV disease. Response rates, calculated on an 'intention to treat' basis, were as follows: MVP, 14.3% (95% CI 5.94-27.2%); PIN, 16.7% (95% CI 7.4-30.2%); and CaN, 14% (95% CI 5.3-27.9%). The overall median survivals were 256, 269 and 243 days for patients treated with MVP, PIN and CaN respectively. Myelosuppression was the most frequent toxicity: grade 3-4 leucopenia was observed in 14.3%, 25% and 18.6% of patients treated with MVP, PIN and CaN respectively. This multicentre phase II randomized trial shows that MVP, PIN and CaN can be administered on an outpatient basis with acceptable toxicities. Unfortunately, the three regimens showed an activity significantly lower than that reported in previous single-institution phase II trials.