Imaging Cancer-Associated Fibroblasts (CAFs) with FAPi PET.

The tumor microenvironment (TME) surrounding tumor cells is a complex and highly dynamic system that promotes tumorigenesis. Cancer-associated fibroblasts (CAFs) are key elements in TME playing a pivotal role in cancer cells' proliferation and metastatic spreading. Considering the high expression of the fibroblast activation protein (FAP) on the cell membrane, CAFs emerged as appealing TME targets, namely for molecular imaging, leading to a pan-tumoral approach. Therefore, FAP inhibitors (FAPis) have recently been developed for PET imaging and radioligand therapy, exploring the clinical application in different tumor sub-types. The present review aimed to describe recent developments regarding radiolabeled FAP inhibitors and evaluate the possible translation of this pan-tumoral approach in clinical practice. At present, the application of FAPi-PET has been explored mainly in single-center studies, generally performed in small and heterogeneous cohorts of oncological patients. However, preliminary results were promising, in particular in low FDG-avid tumors, such as primary liver and gastro-entero-pancreatic cancer, or in regions with an unfavorable tumor-to-background ratio at FDG-PET/CT (i.e., brain), and in radiotherapy planning of head and neck tumors. Further promising results have been obtained in the detection of peritoneal carcinomatosis, especially in ovarian and gastric cancer. Data regarding the theranostics approach are still limited at present, and definitive conclusions about its efficacy cannot be drawn at present. Nevertheless, the use of FAPi-based radio-ligand to treat the TME has been evaluated in first-in-human studies and appears feasible. Although the pan-tumoral approach in molecular imaging showed promising results, its real impact in day-to-day clinical practice has yet to be confirmed, and multi-center prospective studies powered for efficacy are needed.

Land Plus Aquatic Therapy Versus Land-Based Rehabilitation Alone for the Treatment of Freezing of Gait in Parkinson Disease: A Randomized Controlled Trial.

BACKGROUND: Freezing of gait (FOG) is one of the most disabling symptoms of Parkinson disease (PD). Different land-based rehabilitation approaches based on motor and cognitive strategies can be effective in treating FOG. Although there are data about the efficacy of aquatic therapy in ameliorating this phenomenon, no study has explored the combined effect of land-based therapies plus aquatic therapy in patients with PD who have FOG. OBJECTIVE: The objective was to investigate the effectiveness of a multidisciplinary, intensive, motor-cognitive rehabilitation treatment (MIRT) in improving FOG and whether implementation with aquatic therapy (MIRT-AT) adds further benefits. DESIGN: The design consisted of a single-blind, parallel-group, 1:1 allocation ratio, randomized trial. SETTING: The Department of Parkinson Disease, Movement Disorders and Brain Injury Rehabilitation at "Moriggia-Pelascini" Hospital (Gravedona ed Uniti, Como, Italy) was used as the setting. PARTICIPANTS: Sixty hospitalized patients with PD who had FOG in Hoehn and Yahr stage 2 or 5-3 were included. INTERVENTION: Sixty patients with PD + FOG were randomly assigned to 2 groups: 30 underwent a 4-week MIRT and 30 underwent a 4-week MIRT-AT. MEASUREMENTS: The primary outcome measure was the Freezing of Gait Questionnaire; secondary outcome measures were total Unified Parkinson Disease Rating Scale (UPDRS), UPDRS II, UPDRS III, Berg Balance Scale, Timed Up and Go Test, and 6-Minute Walk Test. These measures were assessed both at admission and discharge. RESULTS: Participants in the 2 groups had similar age, sex distribution, Hoehn and Yahr stage, and most-affected side. At baseline, no difference in outcome measures was observed between the 2 groups. After treatment, a significant time effect was observed for all variables in both groups. No significant time × group interaction was observed. A between-group analysis showed nonsignificant differences between values at T1 and values at T0 for all variables. LIMITATIONS: The limitations were the lack of a control group and follow-up. CONCLUSIONS: We showed that a multidisciplinary, intensive, and goal-based rehabilitation treatment, such as MIRT, improves FOG in patients with PD. Although aquatic therapy could be considered a useful approach for treating FOG, it does not add further benefits to this kind of motor-cognitive rehabilitation.

Treadmill Training with Cues and Feedback Improves Gait in People with More Advanced Parkinson's Disease.

BACKGROUND: Gait disturbances in Parkinson's disease (PD) are highly disabling and poorly responsive to drugs, especially in advanced stages. While the efficacy of a treadmill training based on external feedback and cues (treadmill-plus) on gait disturbances in early PD stages is demonstrated, no definitive evidence exists about advanced stages. OBJECTIVE: We aimed to evaluate the feasibility and the effects of a treadmill-plus training on gait disturbances in advanced PD. METHODS: Two hundred and six PD patients from medium to more advanced Hoehn & Yahr stage (stage 2, n = 79, stage 3 n = 74, and stage 4 = 53) who underwent a 4-week treadmill-plus training, were retrospectively identified. All patients were able to walk on a treadmill for one minute at 1.5 km/h, without support. Feasibility was evaluated by measuring safety, adverse events, and attrition rate. The effects of treatment were evaluated by assessing, both at enrolment and at the end of treatment, the on-land, self-paced 6-minute Walking Test (6MWT) and the gait parameters obtained from the treadmill during a 1.5 km/h trial. RESULTS: All patients completed the treadmill-plus training and no adverse events were recorded, even among more disabled patients. After training, we observed a significant improvement in the 6MWT, an increase in step length and a reduction of cadence and step variability in the whole sample. After stratifying patients according to disease stage, we found that patients in more advanced stages experienced the same improvements in all gait parameters as patients in less advanced stages. CONCLUSIONS: Treadmill-plus training is well tolerated and may have a positive impact on many aspects of gait in more advanced PD stages.

Rehabilitation in progressive supranuclear palsy: Effectiveness of two multidisciplinary treatments.

BACKGROUND: to date, there are no medical or surgical treatments for progressive supranuclear palsy (PSP). It is possible to speculate that patients with PSP could benefit from rehabilitative treatments designed for Parkinson's disease, including the use of robot-assisted walking training. OBJECTIVE: to evaluate whether the use of the robotic device Lokomat® is superior in PSP patients to the use of treadmill with visual cues and auditory feedbacks (treadmill-plus) in the context of an aerobic, multidisciplinary, intensive, motor-cognitive and goal-based rehabilitation treatment (MIRT) conceived for Parkinsonian patients. METHODS: we enrolled twenty-four PSP patients. Twelve subjects underwent a 4-week MIRT exploiting the use of the treadmill-plus (MIRT group). Twelve subjects underwent the same treatment, but replacing the treadmill-plus with Lokomat® (MIRT-Lokomat group). Subjects were evaluated with clinical and functional scales at admission and discharge. The primary outcomes were the total PSP Rating Scale (PSPRS) score and its "limb" and "gait" sub-scores. Secondary outcomes were Berg Balance Scale (BBS), Six Minutes Walking test (6MWT) and the number of falls. RESULTS: total PSPRS, PSPRS-gait sub-score, BBS, 6MWT and number of falls improved significantly in both groups (p ≤ 0.003 all, except 6MWT, p = 0.032 and p = 0.018 in MIRT-Lokomat and MIRT group respectively). The PSPRS-limb sub-score improved significantly only in the MIRT group (p = 0.002). A significant difference between groups was observed only for total PSPRS, indicating a slightly better improvement for patients in the MIRT group (p = 0.047). No differences between groups were revealed for the other outcomes, indicating that the effect of rehabilitation was similar in both groups. CONCLUSIONS: Lokomat® training, in comparison with treadmill-plus training, does not provide further benefits in PSP patients undergoing MIRT. Our findings suggest the usefulness of an aerobic, multidisciplinary, intensive, motor-cognitive and goal-based approach for the rehabilitation of patients suffering from such a complex disease as PSP. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov, NCT02109393.