Sonodynamic Therapy: Advances and Challenges in Clinical Translation

Sonodynamic therapy (SDT) consists of the synergetic interaction between ultrasound and a chemical agent. In SDT, the cytotoxicity is triggered by ultrasonic stimuli, notably through cavitation. The unique features of SDT are relevant in the clinical context more than ever: the need for efficacy, accuracy, and safety while being noninvasive and preserving the patient's quality of life. However, despite the promising results of this technique, only a few clinical reports describe the use of SDT. The objective of this article is to provide an extensive overview of the clinical and preclinical research conducted in vivo on SDT, to identify the limitations, and to detail the developed strategies to overcome them.     

Impact of mediastinal lymph node dissection on octogenarians with non-small cell lung cancer

Objective: Impacts of mediastinal lymph node dissection on a patient’s course after pulmonary resection is unclear in octogenarians with non-small cell lung cancer. Methods: Retrospectively identified subjects included 39 octogenarians and 1 nonagenarian, with grades according to the Charlson Comorbidity Index ranging from only 0 to 2. We performed mediastinal lymph node dissection in 19 patients (D group), and just lymph node sampling biopsy in the other 21 (S group). We compared clinicopathologic features and outcome after surgery between both groups. Results: Deterioration of performance status at the time of discharge, evident in 17 patients overall, was significantly more frequent in the D group. Postoperative complications occurred in 27 patients overall and there was no significant difference between the two groups. Survival rates in younger patients at 1, 3, and 5 years were 86, 59, and 49%, respectively; in octogenarians these were 83, 58, and 42% (no significant difference). Nor did survival differ significantly by surgical management of mediastinal lymph nodes; 1-, 3-, and 5-year survival rates were 94, 63, and 40%, respectively in the D group and 78, 66, and 43%, respectively in the S group. Conclusion: Octogenarians with non-small cell lung cancer should be treated by urgent pulmonary resection whenever possible. Since mediastinal lymph node dissection has little effect on long-term survival or the carried risk of worsening performance status at discharge, pulmonary resection without complete mediastinal lymph node dissection should be considered.     

Auditory brainstem responses after out-of-hospital cardiac arrest: Are they useful for outcome prediction?

We evaluated whether we could predict the neurologic outcome in 55 out-of-hospital cardiac arrest patients using auditory brainstem responses (ABR). ABR patterns were classified into one of 3 types by evaluation of 5 components: type 1, with all 5 components; type 2, lack of at least one response between the 2nd and 5th components; type 3, with only the first component or no response. The relation between the ABR patterns on the 3rd day following resuscitation and the neurologic outcome on hospital discharge was evaluated. The specificity that the 5 awake patients had type-1 ABR was 38%. The sensitivity that the 10 brain dead patients had type-3 ABR was 60%. In the type-1 ABR patients, the negative predictive value that the patients were awake was 100%. In the type-3 ABR patients, the negative predictive value that the patients became brain dead was 90.9%. These results suggest that ABR on the 3rd post-resuscitation day may not be useful for predicting if patients are awake or become brain dead, although the loss of components may be a sign of morbidity, and the presence of the 2nd or later components indicates possible future prevention of brain death.     

Monoclonal antibody analysis of glomerular, tubulo-interstitial infiltrating immune cells in various glomerulonephritis

To investigate the role of cell-mediated immunity (CMI) in glomerulonephritis (GN), we identified the infiltrating immune cells both within the glomerulus and in the interstitium. Frozen sections from 103 patients with various forms of GN: 10 with minor glomerular abnormality (MGA) as control, 10 with minimal change nephrotic syndrome (MCNS), 10 with membranous nephropathy (MN), 9 with focal glomerulosclerosis (FGS), 30 with IgA nephropathy (IgAN), 22 with acute post streptococcal glomerulonephritis (APSGN), and 2 with rapidly progressive glomerulonephritis (RPGN) were examined using monoclonal antibodies (MoAb) by indirect immunoalkaline-phosphatase labelling. In most glomerulonephritis, monocyte/M phi and helper/inducer T cells were predominantly infiltrating in the interstitium, but intraglomerular infiltration was rare, except for APSGN. This interstitial infiltration increased proportionally to the level of serum creatinine, and was most prominent in RPGN. Apparently different distribution was seen in APSGN, that is, prominent increase in total number of intra-glomerular monocyte/M phi infiltration with slightly increased T cells. The change was correlated with time after onset; namely the more leucocytic infiltration was observed when the tissue was taken earlier. These data suggest that in APSGN, monocyte/M phi accumulate in glomeruli via cell mediated immunity in addition to humoral immune mechanism resulting in glomerular hypercellularity, whereas in most chronic glomerulonephritis interstitial leucocyte infiltration, particularly helper T cells and monocyte/M phi may play an important role in the progression of glomerulonephritis.     

School-refusal and social-withdrawal in the clinical setting at a psychiatric medical institution]

Fifty two outpatients, who showed signs of school-refusal-withdrawal at the Shiga Prefectural Psychiatric Institution have been analyzed according to their age, gender, ICD-10 diagnosis, medical evolution, and total number of consultations. A total of 61.5% of the population were male, and they showed a higher average and a wider range of age than female patients. According to the ICD-10 diagnosis, 67.3% were in the group of F40-48 neurotic, stress-related and somatoform disorders, and 11.5% were in the group of F30-39 mood [affective] disorders. Twenty five % of the patients were assumed to have show medical improvement, and 42.3% of the patients continued to have further consultations. This article discusses the possible role of psychiatric medical institutions in supporting cases of school-refusal and social-withdrawal.     

The relationship between jaw deformity and scoliosis

Objectives To analyze the relationship between lateral displacement of the mandible and scoliosis. Methods From April 2002 through July 2003, we examined posteroanterior cephalometric radiographs and chest X-rays from 85 patients with jaw deformities and a control group of 20 patients with no jaw deformities. To measure the lateral shift of the mandible, we drew a horizontal baseline (X axis) on the cephalogram connecting the intersection of the external margins of the orbits and the most lateral points of the greater wings of the sphenoid. A vertical baseline (Y axis) was then marked perpendicular to the X axis, intersecting the ethmoid crista galli. Then, we measured the lateral displacement of the mandibular mentum from the Y axis. Displacement to the right was designated positive; that to the left was designated negative. Cobb's method was used to measure scoliosis curves on chest X-rays; the direction of the curve was designated similarly. Results Of the 85 patients with jaw deformity, 23 (27.1%) had a Cobb angle exceeding 10°. None of the control group had scoliosis exceeding 10°. No correlation was found between the direction of mandibular displacement and the direction of scoliosis. Conclusion This study suggests a relationship between jaw deformities and scoliosis, as scoliosis was found in 27.1% of the patients with a main complaint of jaw deformity.     

Cellular interactions in effector cell generation and tumor regression mediated by anti-CD3/interleukin 2-activated tumor-draining lymph node cells.

Previous studies have demonstrated that progressive growth of the weakly immunogenic MCA 106 murine sarcoma stimulated, in the draining lymph nodes, the production of tumor-sensitized but not fully functional preeffector lymphocytes. These lymphocytes could develop into specific immune effector cells after sequential in vitro activation with anti-CD3 monoclonal antibody and interleukin 2 (IL-2). In this study, we analyzed cellular requirements for in vivo sensitization of preeffector cells, for generation of immune effector cells by the method of anti-CD3/IL-2 activation, and for adoptive immunotherapy mediated by activated cells. By selective depletion of T-cell subsets in vivo, we found that tumor regression after systemic adoptive immunotherapy required the collaboration of activated CD4+ and CD8+ cells. It was further demonstrated that CD8+ immune cells alone could mediate antitumor effects if exogenous IL-2 was provided in vivo. These results suggest that CD8+ cells served as immediate effector cells, whereas CD4+ immune cells provided a helper function via the secretion of IL-2. During in vitro anti-CD3/IL-2 activation, generation of effector cells depended on the collaborative interaction between previously sensitized CD4+ and CD8+ preeffector cells. At the stage of in vitro activation, the addition of IL-2 could not substitute the function of CD4+ cells. We next examined whether the sensitization of preeffector cells in the draining lymph nodes required cellular interactions between CD4+ and CD8+ T-cells. By in vivo depletion of T-cell subsets during tumor growth, we found that CD4+ cells were sensitized independently of CD8+ cells. More interestingly, in vivo sensitization of CD8+ preeffector cells also occurred independently in the absence of a CD4+ helper cell response. The lack of T-cell-T-cell interactions in vivo may explain the failure of effector cell generation during progressive tumor growth. Taken together, these results demonstrate that the anti-CD3/IL-2 activation defines an immune response distinct from many previously described mechanisms of antitumor immune responses.