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.
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.
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.
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.
Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, and MedImmune.
COVID and Lung Cancer Calabrò, Luana; Rossi, Giulia; Covre, Alessia ...
Current oncology reports,
11/2021, Letnik:
23, Številka:
11
Journal Article
Recenzirano
Odprti dostop
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.
Summary
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.
Summary Background Monoclonal antibodies to cytotoxic T-lymphocyte antigen 4 (CTLA4) have therapeutic activity in different tumour types. We aimed to investigate the efficacy, safety, and ...immunological activity of the anti-CTLA4 monoclonal antibody, tremelimumab, in advanced malignant mesothelioma. Methods In our open-label, single-arm, phase 2 study, we enrolled patients aged 18 years or older with measurable, unresectable malignant mesothelioma and progressive disease after a first-line platinum-based regimen. Eligible patients had to have a life expectancy of 3 months or more, an Eastern Cooperative Oncology Group performance status of 2 or less, and no history of autoimmune disease. Patients received tremelimumab 15 mg/kg intravenously once every 90 days until progressive disease or severe toxicity. The primary endpoint was the proportion of patients who achieved an objective response (complete or partial response), with a target response rate of 17% according to the modified Response Evaluation Criteria in Solid Tumors (RECIST) for pleural malignant mesothelioma or standard RECIST 1.0 for peritoneal malignant mesothelioma. Analyses were done according to intention to treat. This trial is registered with EudraCT, number 2008-005171-95, and ClinicalTrials.gov , number NCT01649024. Findings Between May 27, 2009, and Jan 10, 2012, we enrolled 29 patients. All patients received at least one dose of tremelimumab (median two doses, range one to nine). No patients had a complete response and two patients (7%) had a durable partial response (one lasting 6 months and one lasting 18 months); one partial response occurred after initial progressive disease. Thus, the study did not reach its primary endpoint. However, we noted disease control in nine (31%) patients and a median progression-free survival of 6·2 months (95% CI 1·3–11·1) and a median overall survival of 10·7 months (0·0–21·9). 27 patients (93%) had at least one grade 1–2 treatment-emergent adverse event (mainly cutaneous rash, pruritus, colitis, or diarrhoea), and four patients (14%) had at least one grade 3–4 treatment-emergent adverse event (two gastrointestinal, one neurological, two hepatic, and one pancreatic). Interpretation Although the effect size was small in our phase 2 trial, tremelimumab seemed to have encouraging clinical activity and an acceptable safety and tolerability profile in previously treated patients with advanced malignant mesothelioma. Funding Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, Pfizer, and Fondazione Buzzi Unicem.
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.
Objective
Clinical and neuroimaging parameters predictive of the changing clinical course of multiple sclerosis (MS) from relapsing–remitting to secondary progressive have not been clarified yet. We ...specifically designed a prospective 5‐year longitudinal study aimed at assessing demographic, clinical, and magnetic resonance imaging (MRI) parameters that could predict the changing clinical course of MS.
Methods
At study entry and after 5 years, clinical and MRI (ie, gray matter and white matter lesions, including spinal cord lesions, and global and regional cortical thinning) parameters were assessed in a training set of 334 consecutive relapsing–remitting MS patients and in an independent validation set of 84 relapsing–remitting MS patients.
Results
Sixty‐six (19.7%) relapsing–remitting MS patients changed their clinical course during the study and entered into the secondary progressive phase. Age (p = 0.001, odds ratio OR = 1.2), cortical lesion volume (p < 0.001,OR = 1.7), and cerebellar cortical volume (p < 0.001, OR = 0.2) at study entry were found to predict the changing clinical course. The model including only these 3 variables correctly identified 252 of 268 (94.0%) patients who maintained the relapsing–remitting course and 58 of 66 (87.8%) patients who became secondary progressive (cross‐validated error rate = 7.2%). When applied on the validation set, the model obtained a similar error rate (8.4%).
Interpretation
A prediction model based on age, cortical lesion load, and cerebellar cortical volume suitably explains the probability of relapsing–remitting MS patients evolving into the progressive phase. Gray matter damage appears to play a pivotal role in determining the changing clinical course of MS. Ann Neurol 2013;74:76–83
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.
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.
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).
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.
Increasing evidence suggests relevant cortical gray matter pathology in patients with Multiple Sclerosis (MS), but how early this pathology begins; its impact on clinical disability and which ...cortical areas are primarily affected needs to be further elucidated.
115 consecutive patients (10 Clinically Isolated Syndrome (CIS), 32 possible MS (p-MS), 42 Relapsing Remitting MS (RR-MS), 31 Secondary Progressive MS (SP-MS)), and 40 age/gender-matched healthy volunteers (HV) underwent a neurological examination and a 1.5 T MRI. Global and regional Cortical Thickness (CTh) measurements, brain parenchyma fraction and T2 lesion load were analyzed.
We found a significant global cortical thinning in p-MS (2.22 +/- 0.09 mm), RR-MS (2.16 +/- 0.10 mm) and SP-MS (1.98 +/- 0.11 mm) compared to CIS (2.51 +/- 0.11 mm) and HV (2.48 +/- 0.08 mm). The correlations between mean CTh and white matter (WM) lesion load was only moderate in MS (r = -0.393, p = 0.03) and absent in p-MS (r = -0.147, p = 0.422). Analysis of regional CTh revealed that the majority of cortical areas were involved not only in MS, but also in p-MS. The type of clinical picture at onset (in particular, pyramidal signs/symptoms and optic neuritis) correlated with atrophy in the corresponding cortical areas.
Cortical thinning is a diffuse and early phenomenon in MS already detectable at clinical onset. It correlates with clinical disability and is partially independent from WM inflammatory pathology.
No second-line treatment significantly prolongs the survival of malignant mesothelioma patients who have a high unmet medical need. Here, we comment on the therapeutic potential of cytotoxic ...T-lymphocyte-associated protein (CTLA)4-blockade by the anti-CTLA4 monoclonal antibody (mAb) tremelimumab of refractory malignant mesothelioma patients. We also focus on the critical role of an accurate tumor assessment in the course of treatment with immunomodulating mAb. Finally, treatment with potentially effective, second-generation checkpoint(s) inhibiting mAb, as well future combination strategies in this deadly disease, will be discussed.
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 mm
2
.
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.
Research report.
To evaluate the anatomical characteristics of the ankle retinacula and their relationship with the fasciae and muscles in healthy subjects and in patients with ankle sprain outcomes.
...The role of the retinacula in proprioception has begun to emerge, but without clear anatomical bases or descriptions of their possible damage in patients with ankle sprain outcomes.
Dissection, histological and immunohistochemical analysis of 27 legs. An in vivo radiological study by MRI was also performed on 7 healthy volunteers, 17 patients with outcomes of ankle sprain, and 3 amputated legs.
The retinacula are thickenings of the deep fascia presenting bone or muscular connections. They are formed of 2-3 layers of parallel collagen fibre bundles, densely packaged with a little loose connective tissue, without elastic fibres but many nervous fibres and corpuscles. By MRI, the retinacula appeared as low-signal-intensity bands with a mean thickness of 1 mm. In patients with outcomes of ankle sprain, MR findings were abnormal retinacula thickness, signal intensity, and full-thickness gap.
The retinacula are not static structures for joint stabilisation, like the ligaments, but a specialisation of the fascia for local spatial proprioception of the movements of foot and ankle. Their anatomical variations and accessory bundles may be viewed as morphological evidence of the integrative role of the fascial system in peripheral control of articular motility.
PDF
