Comprehensive Review of ROS1 Tyrosine Kinase Inhibitors-Classified by Structural Designs and Mutation Spectrum (Solvent Front Mutation [G2032R] and Central ß-Sheet 6 [Cß6] Mutation [L2086F]).

Despite ROS1 fusion-positive NSCLC accounting for approximately 1% to 2% of NSCLC, there is a long list of ROS1 tyrosine kinase inhibitors (TKIs) being developed in addition to three approved ROS1 TKIs, crizotinib, entrectinib and repotrectinib. Here, we categorized ROS1 TKIs by their structures (cyclic versus noncyclic) and inhibitory abilities (active against solvent front mutation G2032R or central ß-sheet #6 [Cß6] mutation L2086F) and summarized their reported clinical activity in order to provide a dashboard on how to use these ROS1 TKIs in various clinical situations. In addition, the less known Cß6 mutation ROS1 L2086F confer resistances to next-generation ROS1 TKIs (repotrectinib, taletrectinib, and potentially NVL-520) that can be overcome by cabozantinib as documented in published patient reports and potentially by certain L-shaped type I ROS1 TKIs including ceritinib and gilteritinib, which is approved as a FLT3 inhibitor for relapsed refractory FLT3+ acute myeloid leukemia but have published preclinical activites against ROS1 (and ALK). Future clinical trials should investigate cabozantinib and gilteritinib to repurpose them as ROS1 TKIs that can target ROS1 L2086F Cß6 mutation.

Meal Eating Characteristics of Patients with Gastroparesis.

BACKGROUND: Patients with gastroparesis often consume only small meals due to early satiety. AIMS: (1) Describe meal eating characteristics of patients with gastroparesis; (2) Relate meal eating characteristics to symptoms, gastric emptying (GE), and body weight. METHODS: Patients with gastroparesis filled out questionnaires including Patient Assessment of Upper GI Symptoms (PAGI-SYM), and questionnaire about meal habits and body weight. Patients underwent gastric emptying scintigraphy. RESULTS: Of 192 gastroparesis patients, 93% endorsed early satiety (ES) with severity of 3.7 ± 1.5 (scored from 0-5) and 93% endorsed postprandial fullness (PPF) with severity of 3.9 ± 1.3. Time spent consuming meals averaged 13.6 ± 17.7 min. Main reasons patients stopped eating were fullness (61%), nausea (48%), and abdominal pain (31%). Time spent eating correlated inversely with severity of nausea (r = -0.18, p < 0.05), stomach fullness (r = -0.21, p < 0.01), PPF (r = -0.23, p < 0.01), loss of appetite (r = -0.34, p < 0.01). Postprandial fullness lasted for 316 ± 344 min. Duration of PPF correlated with nausea (r = 0.30, p < 0.01), retching (r = 0.29, p < 0.01), vomiting (r = 0.28, p < 0.01), stomach fullness (r = 0.33, p < 0.01), loss of appetite (r = 0.35, p < 0.01), and constipation (r = 0.27, p < 0.01). Underweight patients had increased inability to finish a normal size meal (p < 0.01), loss of appetite (p < 0.01), and lower abdominal pain/discomfort (p < 0.05). Patients had lost 3.06 ± 10.60 kgs from their baseline weight. Weight loss correlated with nausea (r = 0.26, p < 0.01), ES (r = 0.30, p < 0.01), loss of appetite (r = 0.28, p < 0.01). CONCLUSIONS: Early satiety and postprandial fullness were common with high severity. The main reasons for meal cessation were early satiety, nausea, and abdominal pain. Body weight and change in body weight were associated with symptoms of gastroparesis.

Ultrasound and analysis of the deformation patterns of the masseter muscle: comparing surgical anatomy, ultrasound and functional anatomy.

PURPOSE: We have tried to demonstrate whether the analysis of the muscle strain allows us to identify the three distinct functional areas of the architecture of the masseter, as one would see them by performing or viewing an anatomical dissection of said muscle, and whether these sections have behave differently in terms of origin and coping of the strain they face (quantitative analysis). MATERIALS AND METHODS: This work has been elaborated by the use of an ultrasound machine (MicrUs ext-1H Telemed Medical Systems Milano) and a linear probe (L12-5l40S-3 5-12 MHz 40 mm) which allowed us to record a 45 frame per second video (DCM). Videos has been elaborated by use of an ultrasound machine (MicrUs ext-1H Telemed Medical Systems Milano) and a linear probe (L12-5l40S-3 5-12 MHz 40 mm) which allowed us to record a 45 frame per second video (DCM). We applied to the resulting video a software (Mudy 1.7.7.2 AMID Sulmona Italy) for the analysis of muscle deformation patters (contraction, dilatation, cross-plane, vertical strain, horizontal strain, vertical shear, horizontal shear, horizontal displacement, vertical displacement). The number of videos of masseter muscles in contraction at maximum exertion due to dental clenching made during this research is around 12,000. Out of these we chose 1,200 videos which examine 200 patients (100 females, 100 males). RESULTS: The deformation pattern analysis of the skeletal muscle on ultrasound basis seems to be an adequate instrument to use during the investigation of the functional structure of the masseter muscle given its ability to highlight the distinct activity of each separate part of the muscle. CONCLUSIONS: Moreover the strain does not apply to the muscle uniformly; instead it varies according to the observed area.

Management and control of isotonic contraction generated stress: evaluation of masseter muscle deformation pattern by means of ecography.

PURPOSE: The objective of the following study is to observe the behavior of the six layers of the masseter during an isometric contraction at maximum exertion with the deformation pattern analysis method. MATERIALS AND METHODS: This study has been conducted by use of an ultrasound machine (MicrUs ext-1H Telemed Medical Systems Milano) and a linear probe (L12-5l40S-3 5-12 MHz 40 mm) which allowed us to record a video (DCM) comprised of 45 frames per second. The probe was fixed to a brace and the patient was asked to clench their teeth as hard as possible, obtain the muscle's maximum exertion, for 5 seconds three times, with 30 seconds intervals in between. Both right and left masseter muscles were analyzed. Then we applied to the resulting video a software (Mudy 1.7.7.2 AMID Sulmona Italy) for the analysis of muscle deformation patterns (contraction, dilatation, cross-plane, vertical strain, horizontal strain, vertical shear, horizontal shear, horizontal displacement, vertical displacement). The number of videos of masseter muscles in contraction at maximum exertion due to dental clenching made during this research is around 12,000. Out of these we chose 1,200 videos which examine 200 patients (100 females, 100 males). RESULTS: The analysis of the deformation patterns of the masseter allows us to observe how the six layers of the muscle have different and specific functions each, which vary depending on the applied force (application point, magnitude and direction) so that we find it impossible to assign to one of the three sections of the muscle a mechanical predominance. Therefore it appears that the three parts of the muscle have specific and synergistic tasks.

Analysis of masseter deformation patterns during a maximum exertion clenching in patients with unilateral chewing.

PURPOSE: The aim of the following study is to examine both masseter muscles (left/right) in a group of patients suffering from unilateral chewing during a maximum exertion isometric contraction using the deformation pattern analysis of ultrasound videos and compare them with the results obtained by studying patients with alternate bilateral chewing patterns. MATERIALS AND METHODS: This study has been conducted by use of an ultrasound machine and a linear probe which allowed us to record a video (DCM) comprised of 45 frames per second (MicrUs ext-1H Telemed Medical Systems Milano) and a linear probe (L12-5l40S-3 5-12 MHz 40 mm). The probe was fixed to a brace and the patients were asked to clench their teeth as hard as possible, obtain the muscle's maximum exertion, for 5 seconds three times, with 30 seconds intervals in between. Both right and left masseter muscles were analyzed. We applied to the ultrasound video a dedicated software (Mudy 1.7.7.2 AMID Sulmona Italy) for the analysis of muscle deformation patterns. The total number of patients for this study is 150. Out of this number, 50 belong to Group A, mono lateral chewing on the left side arch, and 50 to Group B, mono lateral chewing on the right side arch. The remains patients belong to Group C, bilateral alternate chewing. The deformation pattern analysis of the skeletal muscles on ultrasound videos allows us to highlight with ease the clear difference in the clenching capabilities and strain management between the dominant masseter and the subordinate masseter in a unilaterally chewing patient. RESULTS: In the sample investigated both in Group A and Group B the unilateral chewing is associated with a series of parameters (number, shape, volume, position and orientation of the teeth) and is also associated with the extension of the cutting surface really available.

Is the HLA-linked haemochromatosis allele implicated in idiopathic refractory sideroblastic anaemia?

In order to assess the previously reported association of HLA-linked idiopathic haemochromatosis with idiopathic refractory sideroblastic anaemia (IRSA), the prevalence of HLA-A3 antigen in a group of 22 patients with IRSA was compared to that observed in healthy controls and in patients with homozygous idiopathic haemochromatosis and to that calculated for a population heterozygous for idiopathic haemochromatosis. The prevalence of A3 in patients with IRSA (0.23) was quite similar to that observed in controls (0.29) and significantly different from that observed in homozygous (0.73; P less than 10(-5] and heterozygous (0.57; P less than 10(-3] haemochromatosis. Serum iron, transferrin saturation, serum ferritin and liver iron concentration showed no difference in IRSA patients with or without A3. It is concluded that there is neither systematic association between the haemochromatosis allele and IRSA nor systematic implication of such an allele in the development of iron overload observed in IRSA.