Safety profile of immune checkpoint inhibitors: An analysis of the Italian spontaneous reporting system database.

AIMS: To provide an overview of immune checkpoint inhibitors (ICIs) safety profile using the Italian spontaneous adverse drug reaction (ADR) reporting system. METHODS: We selected all ADR reports attributed to ipilimumab (CTLA-4 inhibitor), nivolumab, pembrolizumab, atezolizumab (PD-1/PD-L1 inhibitors) from the Italian spontaneous reporting system (2011-2018). Descriptive analyses of reports for ICIs have been conducted. Time to onset of adverse effects was stratified by system organ class. Reporting odds ratio was used as measure of ADR reporting disproportionality. ICI-related ADR reports were compared with 2 reference groups, i.e. all other suspected drugs or all other antineoplastic agents. RESULTS: Overall, 2217 (0.7%) reports were related to ICIs (nivolumab: 72.2% of those reports; ipilimumab: 14.3%; pembrolizumab: 10.3%; and atezolizumab: 3.5%). ICI-related ADR reports mostly involved males (65%) and median age was 67 (interquartile range 59-73) years. Serious reports accounted for 48.8%. Frequencies of endocrine, general, hepatobiliary, metabolism, musculoskeletal, respiratory disorders, infections and neoplasms were significantly higher for ICIs than for all other drugs (P < .001). Except for infections, similar results emerged through comparison with other anticancer drugs. Colitis, hypophysitis and skin disorders were more frequently reported for anti-CTLA-4 drugs than PD-1/PD-L1 ICIs, and the opposite for musculoskeletal effects, pneumonia, and thyroid dysfunctions. ICIs were disproportionally associated also with less known risks, e.g. ischaemic heart disease, cardiac failure and optic nerve disorders. CONCLUSION: The most frequently reported safety issues were probably immune-related adverse events including general, gastrointestinal and respiratory disorders. Potentially emerging safety signals, such as ischaemic heart disease and cardiac failure, requiring further investigation were detected.

Clinical significance of different effects of static and pulsed electromagnetic fields on human osteoclast cultures.

Electromagnetic fields are known to affect the bone metabolism by modifying some relevant physiologic cell parameters of cells, even though the underlying mechanisms are still unclear. The aim of our study was to evaluate the effect of both static magnetic fields (SMFs) of the same intensity of the one generated by spinal metal devices and pulsed electromagnetic fields (PEMFs) of the same intensity used for the management of nonunion on human osteoclasts cell culture. Primary osteoclast cells were isolated from primary human osteoclast precursors and were exposed to SMFs and to PEMFs. Morphology and tartrate-resistant acid phosphatase (TRAP) activity were evaluated in the osteoclast cultures after 7, 10, and 14 days of exposure. The SMF-exposed cells show a more differentiated phenotype and a significantly higher TRAP activity after 7 and 10 days of treatment with respect to a sham control. PEMF-exposed cells have a less-differentiated phenotype after 7 days of exposure compared with the relative sham control, while the TRAP activity shows no statistically significant differences between exposed and control cells at any observation time. Our results indicate that SMFs of the same intensity of the one generated around spinal devices can affect osteoclast differentiation and activity. Aseptic loosening around titanium implants might be due in part to an increased osteoclast activity and differentiation. PEMFs of the same intensity than the one used for the management of nonunions can affect osteoclasts phenotype after 7 days of exposure, while osteoclasts TRAP activity is not affected by this kind of electromagnetic fields.

'Internal bracing' surgery in the management of solid tumor metastases of the thoracic and lumbar spine.

In patients with thoracolumbar spine metastasis, surgery is aimed at patient healing only when patient has a good prognosis with long life expectancy. In patients with short life expectancy a less aggressive surgical approach of posterior decompression and stabilization could improve patient care and allow for neurological recovery. Thirty-two consecutive patients affected by symptomatic thoracolumbar spine metastases with short life expectancy and good Karnofsky index (50-70) were subjected to surgery and reviewed retrospectively. After tumor embolization, surgery consisted of posterior decompression and stabilization with laminar hooks in the dorsal spine, and laminar hooks or lumbar pedicle screws. Patient's Karnofsky Index, average survival, Frankel neurological status, and pain were recorded before and after surgery, together with surgery related complications. Primary tumors were breast carcinoma (nine patients), renal cell carcinoma (three), lung carcinoma (four), GI tract carcinoma (six), prostate carcinoma (two), carcinoma of the uterus (two), melanoma (three), and malignant tumors at other different sites (three). Average survival after surgery was 23 months, with highest survival rates in renal cancer and breast carcinoma patients, and poorest survival rates in lung and dedifferentiated carcinoma. Karnofsky index improved from average 61 to 72% post-operatively. After surgery patients experienced significant overall improvement of Frankel score and decrease of referred pain. Hospitalization stay was on average 10 days. Results showed that operative treatment of symptomatic spinal metastases in patients with poor prognosis and good general health status improves or preserves neurological function, allows for adjuvant treatments to be performed and has a role in improving general health status in most patients.

Para-articular osteochondroma of the knee.

We report a case of para-articular chondroma located in the infrapatellar fat pad of the knee of a 42-year-old woman with a history of anterior knee pain and restricted range of motion. On clinical examination, a solid palpable mass in the infrapatellar region was detected. Radiography and computed tomography of the knee revealed the presence of 3 different "popcorn"-like gross calcifications within Hoffa's fat pad. Magnetic resonance imaging showed areas of signal intensity in Hoffa's fat pad that were consistent with calcific nodules surrounded by chondral tissue. During arthroscopy, a dense extrasynovial mass was discerned within Hoffa's fat pad. The mass was entirely removed through an open approach medial to the patellar tendon. Resection specimens consisted of 3 well-circumscribed nodules of 5 x 2.5 x 1.5, 2 x 2 x 1, and 1.5 x 2 x 1 cm, respectively. Grossly, these nodules were surrounded by adipose tissue and presented a thin fibrous membrane. Histologic examination showed that the nodules were composed of cartilaginous tissue surrounded by fibrous connective and adipose tissue with multifocal endochondral ossification. The precise pathogenetic mechanism of these tumors remains unknown, but cartilaginous metaplasia of articular and para-articular connective tissue seems to be the primary cause. Patients with these lesions are currently treated with the use of marginal resection or excision.

Effect of pulsed electromagnetic fields on human osteoblast cultures.

BACKGROUND AND PURPOSE: Exogenous electromagnetic fields (EMFs) affect bone metabolism, but the mechanisms responsible for this phenomenon are unclear. Pulsed EMFs (PEMFs) can be effective in the management of congenital pseudarthrosis or delayed union or non-union of fractures. We investigated the effects of PEMFs used in clinical practice on human osteoblast cultures. METHODS: Primary osteoblastic cells were isolated from a human femoral head. Cultures were exposed to the PEMF stimulation for 72 hours, 7 and 10 days and compared with a control group of primary osteoblastic cells non-exposed to PEMF. Cell growth and alkaline phosphatase activity were evaluated in the osteoblast cell cultures at each observation time. RESULTS: At each observation time, the differences in cell numbers between PEMF-exposed cells and control group were statistically significant (p < 0.05). The alkaline phosphatase-specific activity of PEMF-exposed osteoblast cultures showed a statistically significant (p < 0.05) increase when compared with the control group after 7 and 10 days of exposure. CONCLUSIONS: The application of PEMF stimulation on human osteoblasts accelerates cellular proliferation when compared with a control group of non-PEMF-exposed cells.

Effect of pulsed electromagnetic fields on human tenocyte cultures from supraspinatus and quadriceps tendons.

OBJECTIVE: : To investigate the effects of pulsed electromagnetic fields (PEMFs) on human tenocyte cultures and to assess whether PEMFs could represent a viable therapeutic option in tendon pathologies. DESIGN: : Controlled laboratory study in which primary human tenocytes were isolated from healthy supraspinatus and quadriceps tendons and were exposed to the electromagnetic field stimulation. Cell growth and cell cycle were evaluated after 72 hrs, 5 days, and 7 days of continuous PEMF exposure. In quiescent confluent tenocyte culture, an in vitro cut was mechanically produced, and the width of the cell-free zone was measured 12, 24, and 36 hrs after the injury in the presence of PEMF stimulation. Total collagen accumulation was also evaluated after 5, 7, and 14 days of PEMF exposure. RESULTS: : Tenocyte growth analysis, cell cycle analysis, and total collagen accumulation did not show statistically significant differences between exposed and control groups. Exposure to PEMF significantly accelerated cut closure 12 and 24 hrs after the injury. CONCLUSIONS: : PEMFs comparable with the ones used for the management of pseudoarthrosis stimulate closure of an in vitro laceration of a tenocyte monolayer. Our results provide the preliminary in vitro work and the basis to support the study of the in vivo effects of PEMFs on tendinopathies.

Periprosthetic electrochemical corrosion of titanium and titanium-based alloys as a cause of spinal fusion failure.

STUDY DESIGN: Posterior lumbar spine implants retrieved from patients affected by periprosthetic osteolysis were analyzed to identify corrosion and to investigate the electromagnetic fields (EMF) generated by corrosion currents and their effect on human osteoblasts proliferation. OBJECTIVE.: Analysis of retrieved instrumentation to better understand periprosthetic osteolysis and correlation of this information with clinical factors. SUMMARY OF BACKGROUND DATA: Recent studies have pointed out that mechanically assisted crevice corrosion represents the initial failure of spinal implants, resulting in the local decrease in pH, which leads to osteolysis. METHODS: Electrochemical analysis was performed to characterize the corrosion currents and the EMF generated around the implants retrieved. Human primary osteoblasts cultures were used to determine the effect of continued EMF stimulation on cell growth. Cultures were exposed to the EMF stimulation for 48 hours, 72 hours, 7 days, and 14 days. RESULTS: During the electrochemical corrosion tests both the screws and the bar showed a passivation current of 0312 and 0.05 muA/cm, respectively. Osteoblasts exposed to an EMF of 12.1 x 10 T displayed a decreased proliferation rate. At each observation time, there were differences in cell numbers between the unexposed cells and the exposed cells. CONCLUSION: Aseptic periprosthetic bone loss can be due in part to the generation of electric and electromagnetic phenomena generated around metal devices, which inhibit osteoblasts growth and might hamper periprosthetic bone formation. This mechanism is of clinical significance and should be more deeply evaluated.

Static electromagnetic fields generated by corrosion currents inhibit human osteoblast differentiation.

STUDY DESIGN: Human osteoblast cultures were exposed to a very low intensity static magnetic fields (SMF) to investigate its effects on osteoblast growth and differentiation. OBJECTIVE: Analysis of the effects of periprosthetic SMF on the growth and differentiation of human osteoblast cell cultures in vitro. SUMMARY OF BACKGROUND DATA: The effects of pulsed electromagnetic fields (PEMF) on cell proliferation, especially in human osteoblast-like cells is well described, whereas few data are available on the effects of SMF on osteoblast cell culture. We previously demonstrated that the proliferation of human osteoblast cultures is reduced when cells are exposed to a continuous low intensity SMF comparable to the one that occurs around metal devices (Ti spinal implant) because of the generation of electric currents between the screw (Ti6Al4V) and the rod (Ti). METHODS: Primary osteoblastic cells were isolated from a human femoral head. Osteoblast cultures were exposed to SMF and alkaline phosphatase activity was evaluated in the osteoblast cell cultures at different time points. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to evaluate mRNA expression levels of osteocalcin, Runx2, and collagen I genes. RESULTS: The SMF-treated cells showed a progressive increase in the alkaline phosphatase activity which, however, remained always lower than the one observed in the control group at each observation time (72 hours, 7 and 14 days). RT-PCR demonstrated that Runx2 and collagen I mRNA were downregulated following SMF stimulation, whereas no change in osteocalcin mRNA was observed. CONCLUSION: Continuous low-intensity electromagnetic field comparable to the one that generates around metal devices because of the generation of corrosion currents inhibits osteoblasts differentiation pattern and might contribute at least in part to a decrease in periprosthetic bone formation occurring in vivo.

Multiple osteochondroses of bilateral knee joints: a case report.

Knee injuries in young athletes include not only the typical adult bone injuries, ligament and cartilage, but also the growth plate lesions. Osteochondroses are idiopathic, self-limited disturbance of enchondral ossification in which a rapid growth spurt is present. The patella could be affected by two different kinds of osteochondroses: Kohler syndrome and Sinding-Larsen-Johansson. Here we are reporting the first case of simultaneous location of osteochondroses of the two ossification centers of both patella. A 9-year-old boy, competitive skater, presented a history of anterior knee pain involving both knees. Standard X-rays, axial patellar view, MRI and arthro-MR were performed. In order to follow the natural history of the pathology and the evolution of the healing, examinations at 2 years were repeated. We proposed the young skater a medical and a physiotherapeutic treatment based on unloading, isometric exercises, NSAID. As the symptoms improve a gradual return to competitive sports activity was allowed. The case mentioned above can be considered an atypical case because the patient suffered for a bilateral knee osteochondroses, involving simultaneously the primary ossification centre (Kohler syndrome) and the secondary ossification centre (Larsen syndrome) of the patella.