Quantitative 3D-CT imaging of sarcopenia mitigation in the elderly: evidence from a case report.

This case study examines the effectiveness of using combined CT imaging and 3D imaging in monitoring the prevention of sarcopenia through continuous daily exercises in an elderly patient. Using a 256-slice CT scanner with dose reduction technology and advanced muscle segmentation with the open-source software DAFNE, we compared changes in muscle mass and density in a 70-year-old patient in 2014 and in 2023. The obtained images allowed the creation of detailed 3D models for a more accurate and intuitive assessment of the leg musculature. Despite aging, the results of the scans performed at the beginning and end of the study period did not show significant changes in the patient's musculature, suggesting that a persistent Full-Body in-Bed Gym protocol ("Gym Bed" exercise routine) can effectively contribute to maintaining muscle mass and density in the elderly. These preliminary results highlight the potential of advanced imaging techniques not only to diagnose but also to quantify the effectiveness of non-pharmacological interventions against sarcopenia.

COVID and Lung Cancer.

PURPOSE OF REVIEW: Since the past year, the fast spread of coronavirus disease 2019 (COVID-19) has represented a global health threat, especially for cancer patients, that has required an urgent reorganization of clinical activities. Here, we will critically revise the profound impact that the pandemic has generated in lung cancer patients, as well the most significant challenges that oncologists have to face to maintain the highest possible standards in the management of lung cancer patients in the pandemic era. RECENT FINDINGS: Evidences suggested a higher susceptibility and mortality of lung cancer patients due to COVID-19. The hard management of this patient population has been also due to the potential cross interference of anti-tumor drugs on SARS-Cov-2 infection and to the differential diagnosis between COVID-19 pneumonitis and drug-related pneumonitis. COVID-19 pandemic has generated a profound reshaping of oncological activities and the development of recommendations by the oncology scientific community to prioritize anti-tumor treatments for lung cancer patients.

Tremelimumab plus durvalumab retreatment and 4-year outcomes in patients with mesothelioma: a follow-up of the open label, non-randomised, phase 2 NIBIT-MESO-1 study.

BACKGROUND: The NIBIT-MESO-1 study demonstrated the efficacy and safety of tremelimumab combined with durvalumab in patient with unresectable mesothelioma followed up for a median of 52 months [IQR 49-53]. Here, we report 4-year survival and outcomes after retreatment, and the role of tumour mutational burden (TMB) in identifying patients who might have a better outcome in response to combined therapy. METHODS: NIBIT-MESO-1 was an open-label, non-randomised, phase 2 trial of patients with unresectable pleural or peritoneal mesothelioma who received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. In this follow-up study, patients with disease progression following initial clinical benefit-ie, a partial repsonse or stable disease-were eligible for retreatment and with the same doses and schedules for tremelimumab and durvalumab as used in the NIBIT-MESO-1 trial. The primary endpoint, immune-related objective response rate, was evaluated per immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST) or immune-related RECIST 1.1 criteria for patients with pleural or peritoneal malignant mesothelioma, respectively. Key secondary endpoints were overall survival and safety, and TMB was also evaluated post hoc in patients who had tumour tissue available before treatment. The intention-to-treat population was used for analysis of all efficacy endpoints. This study is registered with ClinicalTrials.gov, number NCT02588131. FINDINGS: 40 patients were enrolled in the NIBIT-MESO-1 study between Oct 30, 2015, and Oct 12, 2016. At data cut-off, April 30, 2020, five (13%) of 40 patients were alive, and 35 (88%) patients had died of progressive disease. At a median follow-up of 52 months (IQR 49-53), median overall survival was 16·5 months (95% CI 13·7-19·2). Survival was 20% (eight of 40 patients) at 36 months and 15% (six of 40 patients) and 48 months. 17 (43%) of 40 patients met the criteria for enrolment in the retreatment study and were retreated with at least one dose of tremelimumab and durvalumab. No immune-related objective responses were observed in the 17 retreated patients. Seven (41%) of 17 patients achieved immune-related stable disease. From the start of retreatment to a median follow-up of 24 months (22·0-25·0), median overall survival was 12·5 months (95% CI 0·0-25·8), and survival at 12 months was 52·9%, at 18 months was 35·3%, and at 24 months was 23·5%. There were no grade 3-4 immune-related adverse events in the retreatment cohort. In a post-hoc analysis of 28 patients for whom tumour tissue before treatment was available, patients with a TMB higher than the median value of 8·3 mutations per Mb had a higher median overall survival compared with patients with TMB below the median value, but this difference was non-significant. Moreover, when patients were additionally stratified for ICI retreatment (n=13), there was a significant difference in survival between those with a TMB higher than the median of 8·3 mutations per Mb and those with TMB lower than the median in the retreated cohort (41·3 months vs 17·4 months; p=0·02). INTERPRETATION: Tremelimumab combined with durvalumab was associated with long-term survival in patients with mesothelioma. Retreatment was safe and resulted in clinically meaningful outcomes, thus suggesting its potential application in the clinical practice of mesothalioma patients. FUNDING: NIBIT Foundation, Fondazione AIRC, AstraZeneca.

The discomallear ligament: anatomical, microscopical, and radiologic analysis.

BACKGROUND: Several anatomic relationships between the ear and the temporo-mandibular joint have been proposed to account for the presence of tinnitus during temporo-mandibular disorders. Among the otomandibular structures, the discomallear ligament (DML) is interposed between the malleus and the retrodiscal capsular complex. The aim of present paper was to study through dissection the frequency and morphology of DML, to characterize its type of collagen, and to evaluate the DML on routine computed tomography (CT). METHODS AND RESULTS: The study has been conducted on five un-embalmed adult cadavers, and in all cases, the DML was present (100%). It was constituted mainly by fibers of collagen I, with abundant elastic fibers. On CT exams of 40 patients with no reported pathology of the ear, on axial images, a dense structure, going from the upper end of the petrotympanic fissure to the neck of the malleus, was present in all the cases. In 90%, it showed a triangular shape, in 5% a rectangular shape, and in 5% a curved course. The mean length of the antero-medial side was 2 ± 0.6 mm and that of the antero-lateral side was 1.63 ± 0.5, and the mean area was 1.29 ± 0.83 mm2. CONCLUSION: The DML could represent an anatomical structure that joining the temporo-mandibular joint and the malleus may play a role in the otologic symptoms during temporo-mandibular disorders.

Integration of anatomical and radiological analysis suggests more segments in the human kidney.

An increasing number of observations have called the general scheme of five renal segments into question: anatomists, radiologists, and surgeons have reported discrepancies between Graves's scheme and morphological observations. The aims of the present study are: (1) to assess the correspondence between a virtual and a real vascular cast of the kidney; (2) to analyze the arterial anatomy with reference to the renal segments. Fifteen kidneys were injected with acrylic resins to obtain vascular casts, which were also analyzed by computed tomography. A mean of 6.3 (range 4-8) avascular fissures was found, indicating a mean of 7.3 segments (range 5-9). In the superior and middle territories there was a single segment in 4 (26.7%) and 8 (53.3%) cases, respectively, and there were two segments in 11 (73.3%) and in 7 (46.7%) cases, respectively. In the inferior territory there was a single segment in two cases (13.3%), two segments in nine (60%), and three segments in four (26.7%). A mean segmental volume of 550.5 mm3 was calculated; the posterior (1,030.1 mm3 , 28.9%) and inferior (450.3 mm3 , 24.2%) segments were the largest. More third order branches were identified in the inferior segments than in the other segments (three branches of the inferior segmental artery in 26.6%). According to these data the inferior segment occupies the inferior pole, extending both anteriorly and posteriorly. In conclusion, the high correspondence between a virtual and a real vascular cast permits more segments to be identified than those described by Graves, and the volume of each segment can be calculated. Clin. Anat., 2018. © 2018 Wiley Periodicals, Inc.

Symmetrical Apophyses on the Posterior Margins of the Thyroid Cartilage: A Previously Undescribed Anatomical Variation With Potential Forensic Implications.

Differential diagnosis between normal/variant anatomy and pathological/traumatic findings represents one of the main matters of investigation of the so-called forensic clinical anatomy. In the literature, many anatomical variations of the laryngeal thyroid cartilage have been reported, with potential implications in forensic pathology. They include triticeal cartilages, foramen thyroideum, asymmetry, segmentation or agenesis of the superior thyroid horns, bone connections with the hyoid bone, absence of cricothyroid facets, hypertrophy of the inferior thyroid tubercle, and asymmetries in the thyroid notch, isthmus, or length of the inferior horn. In this report, we describe a laryngeal anatomical variation never described before, consisting of 2 apophyses symmetrically arising from the posterior margins of the thyroid laminae. Postmortem computed tomography performed on the laryngeal visceral block excluded previous traumatic injuries or natural pathologies of the laryngeal cartilages, confirming the congenital origin of the finding. An "omega epiglottis" and 3 laryngeal cysts in the piriform sinuses also coexisted, suggesting the possibility of underlying common developmental mechanisms.

Immune checkpoint blockade therapy of mesothelioma: a clinical and radiological challenge.

Treatment of malignant pleural mesothelioma (MPM) represents a highly unmet medical need. Here, we discuss the results and therapeutic potential of first- and second-generation immunomodulatory antibodies targeting distinct immune checkpoints for the treatment of MPM, as well as their prospective therapeutic role in combination strategies. We also discuss the role of appropriate radiological criteria of response for MPM and the potential need of ad hoc criteria of disease evaluation in MPM patients undergoing treatment with immunotherapeutic agents.

Friar Leopold Mandic (1866-1942): the computed tomography of the body of a saint.

PURPOSE: In forensic clinical anatomy computed tomography (CT) is used in post-mortem radiological investigation as an objective nondestructive documentation of the body surface and of the interior of the body. This technique is applied also in paleopathology, in particular in mummy studies, with the aim of providing a permanent record of the mummy's features, investigating the embalming procedure employed and analyzing the extent of the preservation in detail. METHODS: For the Extraordinary Jubilee of Mercy, the mortal remains of Saint Leopold Mandic and Saint Pio da Pietralcina, as examples of Mercy known by everyone, have been brought to Rome in February 2016. During the survey that preceded the preparation for transport to Rome, a whole-body CT was performed on the mummified corpse of Leopold Mandic, Capuchin Saint of Padova, Italy. RESULTS: The CT examination demonstrated the presence of osteoarthritis at the level of the vertebral column, of the left knee and of the left hand. Moreover, CT showed the preservation of skeleton and partial preservation of the some viscera, such as remnants of the brain, heart, oesophagus, urinary bladder, plexuses and spinal nerves, ear ossicles, major arterial vessels (aorta and carotid arteries). It is to emphasize the fact that Saint Leopold was not subjected before the CT to any conservative treatment. CONCLUSIONS: Computed tomography demonstrated to be a non-destructive method to investigate Saint Leopold, in order to maintain the integrity of the body and to acquire data on his pathologies and on his preservation. CT allows not only the acquisition of sectional images but also, thanks to dedicated software, the post-processing and reconstruction of three-dimensional models, that can be used also for public displays.

The cortical damage, early relapses, and onset of the progressive phase in multiple sclerosis.

OBJECTIVE: To investigate the relationship among cortical radiologic changes, the number of early relapses (ERs), and the long-term course of multiple sclerosis (MS). METHODS: In this cohort study, we assessed the number of cortical lesions (CLs) and white matter (WM) lesions and the cortical thickness (Cth) at clinical onset and after 7.9 mean years among 219 patients with relapsing remitting (RR) MS with 1 (Low-ER), 2 (Mid-ER), and ≥3 (High-ER) ERs during the first 2 years. Kaplan-Meier and Cox regression analyses investigated early factors influencing the risk of secondary progressive (SP) MS. RESULTS: Fifty-nine patients (27%) converted to SPMS in 6.1 mean years. A larger number of CLs at onset predicted a higher risk of SPMS (hazard ratio [HR] 2.16, 4.79, and 12.3 for 2, 5, and 7 CLs, respectively, p < 0.001) and shorter latency to progression. The High-ER compared to the Low-ER and Mid-ER groups had a larger volume of WM lesions and CLs at onset, accrued more CLs, experienced more severe cortical atrophy over time, and entered the SP phase more rapidly. In the multivariate model, older age at onset (HR 1.97, p < 0.001), a larger baseline CL (HR 2.21, p = 0.005) and WM lesion (HR 1.32, p = 0.03) volume, early changes of global Cth (HR 1.36, p = 0.03), and ≥3 ERs (HR 6.08, p < 0.001) independently predicted a higher probability of SP. CONCLUSIONS: Extensive cortical damage at onset is associated with florid inflammatory clinical activity and predisposes to a rapid occurrence of the progressive phase. Age at onset, the number of early attacks, and the extent of baseline focal cortical damage can identify groups at high risk of progression who may benefit from more active therapy.

Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study.

BACKGROUND: Tremelimumab, an anti-CTLA4 monoclonal antibody, initially showed good activity when used alone in patients with mesothelioma, but did not improve the overall survival of patients who failed on first-line or second-line chemotherapy compared with placebo in the DETERMINE study. We aimed to investigate the efficacy and safety of first-line or second-line tremelimumab combined with durvalumab, an anti-PD-L1 monoclonal antibody, in patients with malignant mesothelioma. METHODS: In this open-label, non-randomised, phase 2 trial, patients with unresectable pleural or peritoneal mesothelioma received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. The primary endpoint was the proportion of patients with an immune-related objective response according to the immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST; for pleural mesothelioma) or immune-related RECIST version 1.1 (for peritoneal mesothelioma). The primary analysis was done by intention to treat, whereas the safety analysis included patients who received at least one dose of study drug. This trial is registered with the European Clinical Trials Database, number 2015-001995-23, and ClinicalTrials.gov, number NCT02588131, and is ongoing but no longer recruiting patients. FINDINGS: From Oct 30, 2015, to Oct 12, 2016, 40 patients with mesothelioma were enrolled and received at least one dose each of tremelimumab and durvalumab. Patients were followed-up for a median of 19·2 months (IQR 13·8-20·5). 11 (28%) of 40 patients had an immune-related objective response (all partial responses; confirmed in ten patients), with a median response duration of 16·1 months (IQR 11·5-20·5). 26 (65%) patients had immune-related disease control and 25 (63%) had disease control. Median immune-related progression-free survival was 8·0 months (95% CI 6·7-9·3), median progression-free survival was 5·7 months (1·7-9·7), and median overall survival was 16·6 months (13·1-20·1). Baseline tumour PD-L1 expression did not correlate with the proportion of patients who had an immune-related objective response or immune-related disease control, with immune-related progression-free survival, or with overall survival. 30 (75%) patients experienced treatment-related adverse events of any grade, of whom seven (18%) had grade 3-4 treatment-related adverse events. Treatment-related toxicity was generally manageable and reversible with protocol guidelines. INTERPRETATION: The combination of tremelimumab and durvalumab appeared active, with a good safety profile in patients with mesothelioma, warranting further exploration. FUNDING: Network Italiano per la Bioterapia dei Tumori Foundation, Associazione Italiana per la Ricerca sul Cancro, AstraZeneca, and Istituto Toscano Tumori.

Ischemic colitis following left antegrade sclerotherapy for idiopathic varicocele.

The Tauber procedure, i.e., antegrade sclerotherapy for varicocele, can lead to ischemic colitis. The pathogenesis can involve an atypical systemic-portal communication, which could represent an infrequently reported (rare) anatomical variant. The aim of this study is to review clinical cases from the literature to highlight the anatomical bases of such complications. A computer-aided and hand-checked review of the literature was used to identify relevant publications. Also, the computed tomography (CT) examination of a clinical case with medico-legal implications due to severe vascular complication following Tauber's procedure was reviewed. Although specific references to this complication have appeared since the 19th century, reports in the contemporary literature include only a few clinical cases of ischemic colitis following Tauber's procedure. The CT scan images of a filed lawsuit revealed traces suggesting a significant communication between the testicular and left colic veins, forming part of the systemic-portal anastomoses. An anatomical variation consisting of a communication between the testicular and left colic veins has been described from the clinical point of view, corresponding to a significant anatomical finding identified in the past that has been under-reported and its clinical importance subsequently underestimated. For the first time we have demonstrated its pathophysiological significance in a real clinical scenario, linking the anatomical variation to the clinical complication. This demonstrates the importance of raising scientific awareness on this issue to prevent possibly devastating complications in daily clinical practice. Clin. Anat. 31:774-781, 2018. © 2018 Wiley Periodicals, Inc.

Anatomo-radiological patterns of pancreatic vascularization, with surgical implications: Clinical and anatomical study.

The pancreas receives multiple arterial sources that should be considered in patients undergoing pancreatic surgery. The aim of this study is to describe pancreatic vascularization and to explore the anatomical basis of postoperative complications. Ten specimens from unembalmed cadavers, including the retroperitoneal vessels and organs and spleen, were injected with acrylic resins to obtain vascular casts. Thirty computed tomography angiographies (CTA) of subjects with no pancreatic pathology (mean age 70.9 years) were also analyzed. A paucivascular area at the neck of the pancreas was apparent in all vascular casts. At CTA: (1) the transverse pancreatic artery, the only artery running from the cervicocephalic to the somatocaudal segment, was visible in 76.9% of cases; (2) the splenic artery was suprapancreatic in 66.7% and intrapancreatic with a tortuous course in 33.3%; (3) the posterior superior pancreaticoduodenal artery was visible in 100% of cases, the anterior superior pancreatico-duodenal artery in 92.6%, the anterior inferior pancreaticoduodenal artery in 73.1%, the posterior inferior pancreaticoduodenal artery in 86.4%, the dorsal pancreatic artery in 65.4%, the great pancreatic artery in 73.1%, and the pancreatic arteries to the body and caudal pancreatic arteries in 96.2%. Our study demonstrated great individual variability of the pancreatic vasculature, which can be explored by CTA and could be relevant to surgical procedures. Clin. Anat. 30:614-624, 2017. © 2017 Wiley Periodicals, Inc.

Anatomical study of renal arterial vasculature and its potential impact on partial nephrectomy.

OBJECTIVES: To validate Graves' classification of the intrarenal arteries and to verify the absence of collateral arterial blood supply between different renal segments, in order to maximize peri-operative and functional outcomes of partial nephrectomy. MATERIALS AND METHODS: The study was performed on 15 normal kidneys sampled from eight unembalmed cadavers. Kidneys with the surrounding perirenal fat tissue were removed en bloc with the abdominal segment of the aorta. The renal artery was injected with acrylic and radiopaque resins, with the specimen suspended in water. CT examination of the injected kidneys was performed to analyse the branches located deeply. After imaging acquisition, the specimens were treated with sodium hydroxide for removal of the parenchyma to obtain vascular casts. RESULTS: Ten casts (66.6%) showed the classic subdivision of the main artery into single posterior and anterior branches. With regard to the distribution of the segmental or second-order arteries, only two casts (13%) showed a pattern similar to that described by Graves, characterized by four segmental (second-order) branches coming from the anterior renal artery (apical, superior, middle and inferior). In the remaining 13 kidneys (87%) a different arterial vascular network was detected. In 10 casts (80%) a single renal segment was vascularized by two or more different branches coming from an artery leading to another segment (multiple vascularization). Multiple vascularization was observed in three (20%) apical segments, five (33%) superior segments, six (40%) middle segments, seven (47%) inferior segments and two (13%) posterior segments. CONCLUSIONS: This study shows that in the human kidneys the arterial vasculature is frequently different from that described by Graves. Moreover, in a significant percentage of cases, a single renal segment receives two or more branches that originate from an artery leading to another segment.

Protein Supplementation Does Not Further Increase Latissimus Dorsi Muscle Fiber Hypertrophy after Eight Weeks of Resistance Training in Novice Subjects, but Partially Counteracts the Fast-to-Slow Muscle Fiber Transition.

The response to resistance training and protein supplementation in the latissimus dorsi muscle (LDM) has never been investigated. We investigated the effects of resistance training (RT) and protein supplementation on muscle mass, strength, and fiber characteristics of the LDM. Eighteen healthy young subjects were randomly assigned to a progressive eight-week RT program with a normal protein diet (NP) or high protein diet (HP) (NP 0.85 vs. HP 1.8 g of protein·kg(-1)·day(-1)). One repetition maximum tests, magnetic resonance imaging for cross-sectional muscle area (CSA), body composition, and single muscle fibers mechanical and phenotype characteristics were measured. RT induced a significant gain in strength (+17%, p < 0.0001), whole muscle CSA (p = 0.024), and single muscle fibers CSA (p < 0.05) of LDM in all subjects. Fiber isometric force increased in proportion to CSA (+22%, p < 0.005) and thus no change in specific tension occurred. A significant transition from 2X to 2A myosin expression was induced by training. The protein supplementation showed no significant effects on all measured outcomes except for a smaller reduction of 2X myosin expression. Our results suggest that in LDM protein supplementation does not further enhance RT-induced muscle fiber hypertrophy nor influence mechanic muscle fiber characteristics but partially counteracts the fast-to-slow fiber shift.

Double origin of the superior cerebellar artery associated with homolateral haemorrhagic infarction of cerebellum.

The superior cerebellar artery (SCA) shows the least variable course and the lowest incidence of anatomical variations among cerebellar arteries. In the present study, an 84-year-old woman was affected by a cerebellar infarction which underwent haemorrhagic evolution in the following days. Neuroimaging investigations also showed a probable double origin of the left SCA. Neuropathological examination confirmed the presence of a large haemorrhagic infarction at the level of the superior portion of the left cerebellar hemisphere and vermis. The left SCA arose from two small arteries arising from the left aspect of the basilar artery and joining together after a course of 9 mm. Previous studies have reported the association of cerebrovascular pathologies, such as intracranial aneurysms, with fenestrations and double origins of the posterior inferior cerebellar artery. In the present case, the occurrence of an haemorrhagic infarction in the vascular field of an SCA with double origin is intriguing in suggesting a possible pathophysiological association.

The anterolateral ligament of the knee: a radiologic and histotopographic study.

PURPOSE: Recent anatomic investigations of the lateral structures of the knee have rediscovered a ligament, called the antero-lateral ligament (ALL). METHODS: Ten specimens of ALL (6 M, 4 F, mean age 82.3) were sampled from bodies of the Body Donation program of the University of Padova for histological and immuno-histochemical studies. Moreover, a retrospective magnetic resonance (MR) study was carried out in 50 patients (30 M, 20 F, mean age 37.5). MR exams with a normal anatomo-radiological report were selected. RESULTS: From the microscopic point of view the ALL corresponds to a dense connective tissue (mean thickness 893 ± 423 µm), and is composed by collagen I (90 %), collagen III (5 %) and collagen VI (3 %) and scarce elastic fibers (<1 %). On MR exams, ALL appears as a thin linear structure, originating at the lateral epicondyle, running obliquely downwards and forwards, and inserting in the middle third (46 %) or inferior third (14 %) of lateral meniscus and in the lateral aspect of the proximal tibia. It was observed in 47 cases (93 %), with a mean length of 32 ± 4.6 mm and mean thickness of 1.1 ± 0.4 mm. The ALL showed low signal intensity on both T1- and T2-weighted sequences. CONCLUSION: The ALL shows the typical structure of a fibrous ligament. From the anatomo-radiological point of view the ALL is almost constantly depicted by routine 1.5-T MR scan.

Clinical anatomy of the orbitomeningeal foramina: variational anatomy of the canals connecting the orbit with the cranial cavity.

PURPOSE: In addition to the optic canal and the superior orbital fissure, orbits are connected with the cranial cavity via inconstant canals including the orbitomeningeal foramen. This study has been carried out in order to define many anatomical and radiological details of the orbitomeningeal foramen that are relevant in the clinical practice. METHODS: Almost 1000 skulls and 50 computerized tomographies were examined to determine incidence, number, length, and caliber of the orbitomeningeal foramen as well as the topography of their orbital and cranial openings. A retrospective study of angiographies carried out on more than 100 children was performed to look for arteries candidate to run through the orbitomeningeal foramen. RESULTS: Orbitomeningeal foramina were detected in 59.46% of skulls and in 54% of individuals by computerized tomography. Orbits with two to five foramina were found. Canals were classified as M-subtype or A-subtype depending on their cranial opening. Large foramina, with the caliber ranging between 1 and 3 mm, were found in 12.17% of orbitomeningeal foramen-bearing orbits. By computed tomography the average caliber measured 1.2 ± 0.3 and 1.5 ± 0.5 mm (p < 0.005) at the orbital and cranial openings, respectively (p < 0.005). Angiographies showed meningo-lacrimal and meningo-ophthalmic arteries, meningeal branches of the lacrimal and supraorbital arteries, and some unidentified arteries that could pass through the orbitomeningeal foramina. CONCLUSIONS: Orbitomeningeal foramina are a common occurrence. When large they may house important arteries that can be the source of severe bleedings during deep dissection of the lateral wall of the orbit. Orbital surgeons should be aware of their existence.

Regional Distribution and Evolution of Gray Matter Damage in Different Populations of Multiple Sclerosis Patients.

BACKGROUND: Both gray-matter (GM) atrophy and lesions occur from the earliest stages of Multiple Sclerosis (MS) and are one of the major determinants of long-term clinical outcomes. Nevertheless, the relationship between focal and diffuse GM damage has not been clarified yet. Here we investigate the regional distribution and temporal evolution of cortical thinning and how it is influenced by the local appearance of new GM lesions at different stages of the disease in different populations of MS patients. METHODS: We studied twenty MS patients with clinically isolated syndrome (CIS), 27 with early relapsing-remitting MS (RRMS, disease duration <5 years), 29 with late RRMS (disease duration ≥ 5 years) and 20 with secondary-progressive MS (SPMS). The distribution and evolution of regional cortical thickness and GM lesions were assessed during 5-year follow-up. RESULTS: The results showed that new lesions appeared more frequently in hippocampus and parahippocampal gyri (9.1%), insula (8.9%), cingulate cortex (8.3%), superior frontal gyrus (8.1%), and cerebellum (6.5%). The aforementioned regions showed the greatest reduction in thickness/volume, although (several) differences were observed across subgroups. The correlation between the appearance of new cortical lesions and cortical thinning was stronger in CIS (r2 = 50.0, p<0.001) and in early RRMS (r2 = 52.3, p<0.001), compared to late RRMS (r2 = 25.5, p<0.001) and SPMS (r2 = 6.3, p = 0.133). CONCLUSIONS: We conclude that GM atrophy and lesions appear to be different signatures of cortical disease in MS having in common overlapping spatio-temporal distribution patterns. However, the correlation between focal and diffuse damage is only moderate and more evident in the early phase of the disease.

Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study.

BACKGROUND: CTLA4 blockade by tremelimumab 15 mg/kg every 90 days provided preliminary evidence of activity in patients with pretreated malignant mesothelioma; however, retrospective exposure-response analysis of data from patients with melanoma suggested that this schedule could result in underexposure to tremelimumab. We therefore investigated the efficacy and safety of an intensified schedule of tremelimumab in patients with advanced malignant mesothelioma. METHODS: In this open-label, single-arm, phase 2 study, participants aged 18 years or older with unresectable, advanced malignant mesothelioma (measurable in accordance with the Response Evaluation Criteria in Solid Tumors [RECIST]), a life expectancy of 3 months or more, an Eastern Cooperative Oncology Group performance status of 2 or less, and who had failed a first-line platinum-based regimen were enrolled at the University Hospital of Siena, Siena, Italy. Participants received tremelimumab 10 mg/kg once every 4 weeks for six doses, then every 12 weeks until disease progression, unacceptable toxic effects, or refusal to continue treatment. The primary endpoint was the proportion of patients achieving an immune-related objective response (complete or partial), assessed in all patients who received at least one dose of the study drug. This study is registered with the European Union Clinical Trials Register, number 2012-002762-12, and ClinicalTrials.gov, number NCT01655888. FINDINGS: Between July 30, 2012, and July 15, 2013, we enrolled 29 patients with a median age of 65 years (range 42-78), stage III (n=11) or IV (n=18) disease, and an Eastern Cooperative Oncology Group performance status of 0-1 (n=23) or 2 (n=6). Malignant mesothelioma histology was epithelioid (n=21, including one peritoneal), biphasic (n=6), sarcomatoid (n=1), or undefined (n=1). Patients received a median of six doses of tremelimumab (range 1-13). After a median follow-up of 21·3 months (IQR 18·7-25·9), four immune-related-partial responses were recorded, one at the first tumour assessment (after about 12 weeks) and three at the second tumour assessment (about 24 weeks), with two responses occurring after initial progressive disease and one response after initial stable disease. 15 (52%) of patients achieved disease control, with a median duration of 10·9 months (95% CI 8·2-13·6). According to modified RECIST, one patient (3%) achieved a partial response and 11 (38%) patients achieved disease control rate. Grade 1-2 treatment-related adverse events occurred in 26 (90%) patients and grade 3-4 adverse events in two (7%) patients. The most common treatment-related adverse events were gastrointestinal, dermatological, and fever. INTERPRETATION: Our results suggest that the intensified schedule of tremelimumab investigated seems to have clinical and immunological activity in patients with advanced malignant mesothelioma, and a good safety profile. The same intensified schedule is now being investigated in an ongoing randomised, double-blind, placebo-controlled, phase 2b study. FUNDING: Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, and MedImmune.