Immunotherapy and Targeted Therapy for Small Cell Lung Cancer: There Is Hope

Small cell lung cancer (SCLC) is a devastating and aggressive neuroendocrine carcinoma of the lung. It accounts for ~15% of lung cancer mortality and has had no improvement in standard treatment options for nearly 30 years. However, there is now hope for change with new therapies and modalities of therapy. Immunotherapies and checkpoint inhibitors are entering clinical practice, selected targeted therapies show promise, and “smart bomb”-based drug/radioconjugates have led to good response in early clinical trials. Additionally, new research insights into the genetics and tumor heterogeneity of SCLC alongside the availability of new tools such as patient-derived or circulating tumor cell xenografts offer the potential to shine light on this beshadowed cancer.     

Axial synergies during human upper trunk bending

Upper trunk bending movements were accompanied by opposite movements of the lower body segments. These axial kinematic synergies maintained equilibrium during the movement performance by stabilizing the center of gravity (CG), which shifted on average across all the subjects by 1±4 cm in the anteroposterior direction and thus always remained within the support area. The aim of the present investigation was to provide an insight into the central control responsible for the performance of these synergies. The kinematic analysis was performed by the method of principal components (PC) analysis applied to the covariation between ankle, knee and hip joint angles and compared with CG shifts during upper trunk bending. Subjects were asked to perform backward or forward upper trunk bending in response to a tone. They were instructed to move as fast as possible or slowly (2 s), with high or low movement amplitudes. PC analysis showed a strong correlation between hip, knee and ankle joint changes. The first principal component (PC1) representing a multijoint movement with fixed ratios between joint angular changes, accounted, on average, for 99.7%±0.2% of the total angular variance in the forward trunk movements and for 98.4%±1.4% in the backward movements. The instructed voluntary regulation of the amplitude and velocity of the movement was achieved by adapting the bell-shaped profile of the velocity time course without changes in interjoint angular relations. Fixed ratios between changes in joint angles, represented by PC1, ensured localization of the CG within the support area during trunk bending. The ratios given by PC1 showed highly significant dependence on subjects, suggesting the adaptability of the central control to each subject’s biomechanical peculiarities. Subject’s intertrial variability of PC1 ratios was small, suggesting a stereotyped automatic interjoint coordination. When changing velocity and amplitude of the movement, the ratios remained the same in about half the subjects while in others slight variations were observed. A weak second principal component (PC2) was shown only for fast movements. In forward movements PC2 reflected the early knee flexion that seems related to the disturbances caused by the passive interaction between body segments, rather than to the effect of a central command. In fast backward movements, PC2 reflected the delay in hip extension relative to the movement onset in the ankle and knee that mirrors intersubject differences in the initiation process of the axial synergy. The results suggest that PC1 reflects the centrally controlled multijoint movement, defining the time course and amplitude of the movement and fixing the ratios between changes in joint angles. They support the hypothesis that the axial kinematic synergies result from a central automatic control that stabilizes the CG shift in the anteroposterior direction while performing the upper trunk bending. Received: 8 August 1996 / Accepted: 7 July 1997     

Immune hemolytic anemia associated with tolmetin and suprofen

This article reports the first case of immune hemolytic anemia possibly associated with the ingestion of suprofen. The patient suffered from massive hemoglobinuria and acute renal failure. Serologic studies of the patient's serum revealed suprofen-dependent red cell antibodies. However, tolmetin-dependent antibodies were also found in the serum, showing the same properties as the suprofen antibodies and an even higher titer. The patient not only had drug-dependent antibodies in the serum, but also had developed autoantibodies, a phenomenon that has been described for several other drugs. The working mechanism by which suprofen and tolmetin caused immune hemolysis had properties of both the immune complex model and the induction of autoimmunity. Although it was unclear whether the immune hemolytic anemia was the result of suprofen, tolmetin, or cross-reacting antibodies, we feel that suprofen should be added to the list of nonsteroidal anti-inflammatory drugs associated with a positive direct antiglobulin test.     

Hemorrhagic tumor necrosis during a pilot trial of tumor necrosis factor-alpha and anti-GD3 ganglioside monoclonal antibody in patients with metastatic melanoma

Hemorrhagic tumor necrosis is an inflammatory event that leads to selective destruction of malignant tissues, with both potentially toxic and beneficial consequences. A pilot clinical trial was undertaken combining tumor necrosis factor-alpha (TNF-alpha) with the monoclonal antibody R24 (MoAb R24) against GD3 ganglioside in patients with metastatic melanoma. Patients received MoAb R24 to recruit leukocytes to the tumor followed by low doses of recombinant TNF-alpha to activate leukocytes. Eight patients were treated and seven patients had mild toxicity. One patient with extensive metastatic melanoma developed tumor lysis syndrome within hours after treatment with almost complete necrosis of bulky tumors in multiple visceral sites. To our knowledge, this is the first documented case of hemorrhagic tumor necrosis in a patient with metastatic cancer in multiple visceral sites.     

Coordination between equilibrium and head-trunk orientation during leg movement: a new strategy build up by training.

1. During unilateral leg movements performed while standing, it is necessary to displace the center of gravity toward the other leg to maintain equilibrium. In addition, the orientation of particular segments, such as the head and trunk, which are used as reference values for organizing the motor act, needs to be preserved. The aim of the present study was to investigate the coordination between movement, equilibrium, and local posture. 2. Experiments were carried out on standing subjects who were instructed to raise one leg laterally to an angle of 45 degrees in response to a light. Two sources of light placed in front of the subject indicated the side on which the movement was to be performed. Three main aspects of the posturokinetic sequence were investigated in two populations, naive subjects and dancers: 1) The body weight transfer toward the supporting leg was found to have two components: first, a "ballistic" one, initiated by a thrust exerted by the moving leg; and second, an "adjustment" component during which the displacement of the center of gravity (CG) reaches a final position (steady state). An early burst in the gastrocnemius medialis of the moving leg often precedes the onset of the center of pressure change. Two differences between naive subjects and dancers were observed: first, the new CG position was almost reached in one step very near to the end of the ballistic component and required only a short adjustment in dancers, whereas in naive subjects it was reached in two steps, including a much longer adjustment component. Second, the dancers were able to minimize the CG displacement toward the supporting side; this might be because they form a better internal representation of the biomechanical limits of stability because of their long training. 2) The onset of the lateral displacement of the malleolus marker of the moving leg always occurred when the body weight had almost completed its transfer to above the support foot. This shows that the positioning of the CG in a new position compatible with equilibrium maintenance was a prerequisite for the leg movement to be performed. The relative timing of events during the posturokinetic sequence was fairly fixed in the dancers, whereas it varied from one trial to another in the naive subjects. 3) The coordination between movement, equilibrium, and head-trunk orientation involves two control strategies. An "inclination" strategy was used by the naive subjects; this consisted of an external rotation of the supporting leg around the anteroposterior ankle joint axis. A counter-rotation at the neck level ensured the stability of the interorbital line in the horizontal plane.(ABSTRACT TRUNCATED AT 400 WORDS)