Performance evaluation of adaptive aperture's static and dynamic collimation in a compact pencil beam scanning proton therapy system: A dosimetric comparison study for multiple disease sites

A compact pencil beam scanning (PBS) proton therapy system, Mevion S250i with Hyperscan, is equipped with adaptive aperture (AA) to collimate the beam with 2 different techniques: Static aperture (SA) and dynamic aperture (DA). SA (single aperture) collimates the outermost contour of the target and DA (multi-layer aperture) collimates each energy layer of the proton beam. This study evaluates dosimetric performance of SA and DA for different disease sites. This study includes 5 disease sites (brain, head and neck (HN), partial breast, lung, and prostate), and 8 patients for each. A total of 80 patient treatment plans (5 sites × 8 patients per site × 2 collimation techniques) were created using 2 to 4 proton beams. Both SA and DA plans were made using the same plan and optimization parameters calculated by a Monte Carlo dose algorithm. Multi-field optimization (MFO) was used for HN treatment plans, whereas treatment plans for the other sites were made with single-field optimization (SFO). All plans were robustly optimized with 3 mm (brain and HN) or 5 mm (breast, lung, and prostate) position uncertainty along with 3.5% range uncertainty. Treatment plans were normalized such that 99% of the clinical target volume (CTV) received 100% of the prescribed dose. Dose volume histogram (DVH) parameters were evaluated for CTV and organs at risk (OARs). The CTV was also evaluated for dose homogeneity, dose conformity, and dose gradient. In general, the DA plan made CTV hotter, while it saved OARs better. DA produced better conformity with sharper dose falloff around CTV, while SA generated better homogenous target coverage. DA decreased D_max to brainstem (1.2% = [(SA-DA)/DA × 100%]) for brain, D_max to the spinal cord (137.3%) for HN, D_1% of the ipsilateral lung (50.5%) for breast, and D_max to the spinal cord (74.0%) for lung. The dose reduction in bladder and rectum for prostate plans with DA was less than 2.5%. The DA plans reduced the dose to OARs for all disease sites but escalated the target maximum dose for the same target coverage than the SA plans. The OAR saving and dose escalation depended on CTV size, proximity of the OARs to CTV, and the plan complexity.     

Functional Cloning of Recurrence-specific Antigens Identifies Molecular Targets to Treat Tumor Relapse

Aggressive regrowth of recurrent tumors following treatment-induced dormancy represents a major clinical challenge for treatment of malignant disease. We reported previously that recurrent prostate tumors, which underwent complete macroscopic regression followed by aggressive regrowth, could be cured with a vesicular stomatitis virus (VSV)–expressed cDNA library derived from recurrent tumor cells. By screening the protective, recurrence-derived VSV-cDNA library, here we identify topoisomerase-IIα (TOPO-IIα) as a recurrence-specific tumor antigen against which tolerance can be broken. Tumor recurrences, in two different types of tumor (prostate and melanoma), which had evaded two different frontline treatments (immunotherapy or chemotherapy), significantly overexpressed TOPO-IIα compared with their primary tumor counterparts, which conferred a novel sensitivity to doxorubicin (DOX) chemotherapy upon the recurrent tumors. This was exploited in vivo using combination therapies to cure mice, which would otherwise have relapsed, after suboptimal primary therapy in both models. Our data show that recurrent tumors—across histologies and primary treatments—express distinct antigens compared with the primary tumor which can be identified using the VSV-cDNA library technology. These results suggest that it may be possible to design a few common second-line therapies against a variety of tumor recurrences, in some cases using agents with no obvious activity against the primary tumor.     

Cytokine Conditioning Enhances Systemic Delivery and Therapy of an Oncolytic Virus

Optimum clinical protocols require systemic delivery of oncolytic viruses in the presence of an intact immune system. We show that preconditioning with immune modulators, or loading virus onto carrier cells ex vivo, enhances virus-mediated antitumor activity. Our early trials of systemic reovirus delivery showed that after infusion reovirus could be recovered from blood cells—but not from plasma—suggesting that rapid association with blood cells may protect virus from neutralizing antibody. We therefore postulated that stimulation of potential carrier cells directly in vivo before intravenous viral delivery would enhance delivery of cell-associated virus to tumor. We show that mobilization of the CD11b⁺ cell compartment by granulocyte macrophage-colony stimulating factor immediately before intravenous reovirus, eliminated detectable tumor in mice with small B16 melanomas, and achieved highly significant therapy in mice bearing well-established tumors. Unexpectedly, cytokine conditioning therapy was most effective in the presence of preexisting neutralizing antibody. Consistent with this, reovirus bound by neutralizing antibody effectively accessed monocytes/macrophages and was handed off to tumor cells. Thus, preconditioning with cytokine stimulated recipient cells in vivo for enhanced viral delivery to tumors. Moreover, preexisting neutralizing antibody to an oncolytic virus may, therefore, even be exploited for systemic delivery to tumors in the clinic.     

Calcium insensitivity of FA-6, a cell line derived from a pancreatic cancer associated with humoral hypercalcemia, is mediated by the significantly reduced expression of the Calcium Sensitive Receptor transduction component p38 MAPK

The Calcium-Sensing Receptor is a key component of Calcium/Parathyroid hormone homeostatic system that helps maintain appropriate plasma Ca²⁺ concentrations. It also has a number of non-homeostatic functions, including cell cycle regulation through the p38 MAPK pathway, and recent studies have indicated that it is required for Ca²⁺ mediated growth arrest in pancreatic carcinoma cells. Some pancreatic cancers produce pathogenic amounts of parathyroid like hormones, however, which significantly increase Ca²⁺ plasma concentrations and might be expected to block further cell growth. In this study we have investigated the expression and function of the p38 MAPK signaling pathway in Ca²⁺ sensitive (T3M-4) and insensitive (FA6) pancreatic cancer cell lines. FA-6 cells, which are derived from a pancreatic adenocarcinoma that secretes a parathyroid hormone related peptide, exhibit only very low levels of p38 MAPK expression, relative to T3M-4 cells. Transfecting FA-6 cells with a p38 MAPK expression construct greatly increases their sensitivity to Ca²⁺. Furthermore, the reduction of p38 MAPK in T3M-4 cells significantly reduces the extent to which high levels of Ca²⁺ inhibit proliferation. These results suggest that the low levels of p38 MAPK expression in FA-6 cells may serve to reduce their sensitivity to high concentrations of external Ca²⁺ that would otherwise block proliferation.     

Health-related quality of life and supportive care in patients with rare long-term neurological conditions

Purpose

Rare long-term neurological conditions (rLTNCs) may have significant impact on patients’ health-related quality of life (HRQL); however, evidence is sparse. We assessed HRQL and access to supportive care in patients with rLTNCs.

Methods

Survey of patients with rare rLTNCs (motor neurone disease, Huntington’s disease, cerebellar ataxia, progressive supranuclear palsy, multiple system atrophy, Charcot–Marie–Tooth disease and postpolio syndrome) to assess current access to health and social care, and HRQL using the Euroqol EQ-5D.

Results

A total of 266 participants with rLTNCs completed the survey. The HRQL of patients is substantially reduced compared to the general population. Many patients reported pain, were anxious or depressed and experienced problems with mobility, self-care and usual activities (mean EQ-5D index scores ranged from 0.2 to 0.44). Although some patients have accessed rehabilitative services, results suggest care coordination could be improved.

Conclusions

Rare long-term neurological conditions have a significant impact on HRQL. Many patients with rLTNCs do not seem to be accessing the level of health and social care services that could improve their HRQL.     

Targeted therapy for advanced renal cell cancer: cytokines and beyond

For the past 20 years cytokines have been the mainstay of treatment for advanced renal cell cancer (RCC), despite low response rates achieved and the high toxicity profile observed. The recent advances in molecular biology and the greater understanding of the von Hippel-Lindau (VHL) hypoxia-inducible factor (HIF)-hypoxia-induced gene pathway have paved the way for a plethora of novel agents that selectively inhibit key molecular events which allow the malignant process to continue. The high specificity of targeted agents should allow sparing of healthy cells thereby making them less toxic and well tolerated. However, new and unanticipated toxicities have been described with virtually all new agents, some of which may even be of a similar magnitude to cytokine therapy. Although several agents have demonstrated promising results in clinical trials, especially in terms of disease stabilization, and achieved clinical licences, issues of optimal administration regimens as well as the possible synergy when combined together are currently being explored. In this new era, IL-2 may still have a relevant role in selected subgroups of patients as well in combination with novel agents. Our review describes thoroughly the existing targeted therapies for RCC, presenting the recent clinical data and discussing the perspectives.     

Postprandial Changes in Superoxide Dismutase Activity in Subjects with Gilles de la Tourette Syndrome and Controls

Erythrocyte measures of copper-zinc superoxide dismutase (CuZnSOD) were performed on 11 subjects with a clinical diagnosis of Gilles de la Tourette syndrome (GTS) and 6 healthy controls at specified intervals throughout the day. There were no significant differences between GTS subjects and controls but in both subjects and controls there was a significant increase in SOD, 75 min postprandially, which decreased to baseline 135 min postprandially. This has implications for the timing of biological samples in future studies of SOD. Possible reasons for the increase are discussed.     

Cryopreservation of immature monocyte-derived dendritic cells results in enhanced cell maturation but reduced endocytic activity and efficiency of adenoviral transduction

To date, phase I/II dendritic cell (DC)-based cancer vaccine trials have required repeated venesection or leukapheresis to generate the DCs. Previous studies have suggested that DCs may be cryopreserved and revived for clinical use as sequential immunisations. We have developed a method of cryopreserving monocyte-derived DCs, reviving the cells with minimal loss, and have performed immunophenotypic and functional comparisons of freeze-thawed DCs with their fresh counterparts. We found that the freeze-thawing process itself is efficient in terms of DC recovery, results in semimaturation and reduced endocytic activity, but does not impair the capacity of the DCs to achieve full maturation. Revived cells also showed enhanced allostimulatory activity and antigen-specific responses. After freeze-thawing, DCs produced lower levels of IL-12 p40 and IL-12 p70 on maturation compared to fresh DCs with little change in concentration over 72 h. Genetic modification of DCs by adenoviral transduction was possible after cryopreservation albeit at a lower efficiency of gene transfer than with fresh cells. We conclude that cryopreservation of DCs for clinical immunotherapy is feasible. Modification of cells by pulsing or genetic transfer should take place prior to cryopreservation as the freeze-thawing process itself leads to increased maturation, reduction in endocytic activity but enhanced allostimulatory activity and antigen-specific responses.