Robust rat pulmonary radioprotection by a lipophilic Mn N-alkylpyridylporphyrin, MnTnHex-2-PyP(5+).

With the goal to enhance the distribution of cationic Mn porphyrins within mitochondria, the lipophilic Mn(III)meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP(5+) has been synthesized and tested in several different model of diseases, where it shows remarkable efficacy at as low as 50 µg/kg single or multiple doses. Yet, in a rat lung radioprotection study, at higher 0.6-1 mg/kg doses, due to its high accumulation and micellar character, it became toxic. To avoid the toxicity, herein the pulmonary radioprotection of MnTnHex-2-PyP(5+) was assessed at 50 µg/kg. Fischer rats were irradiated to their right hemithorax (28 Gy) and treated with 0.05 mg/kg/day of MnTnHex-2-PyP(5+) for 2 weeks by subcutaneously-implanted osmotic pumps, starting at 2 h post-radiation. The body weights and breathing frequencies were followed for 10 weeks post-radiation, when the histopathology and immunohistochemistry were assessed. Impact of MnTnHex-2-PyP(5+) on macrophage recruitment (ED-1), DNA oxidative damage (8-OHdG), TGF-ß1, VEGF(A) and HIF-1α were measured. MnTnHex-2-PyP(5+) significantly decreased radiation-induced lung histopathological (H&E staining) and functional damage (breathing frequencies), suppressed oxidative stress directly (8-OHdG), or indirectly, affecting TGF-ß1, VEGF (A) and HIF-1α pathways. The magnitude of the therapeutic effects is similar to the effects demonstrated under same experimental conditions with 120-fold higher dose of ~5000-fold less lipophilic Mn(III)meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP(5+).

Are three doses of stereotactic ablative radiotherapy (SABR) more effective than 30 doses of conventional radiotherapy?

In early stage non-small cell lung cancer (NSCLC) definitive radiation therapy is an appropriate alternative to surgery. Recent studies show, that in such patients hypofractionation schedules (for example 3 times 18 Gy or 5 times 12 Gy), can be safely applied, without causing severe toxicities and achieving high local control rates of up to 90% and more. In the last couple of years a lot of knowledge about the cancer biology, technical aspects, clinical outcomes and toxicities has been accumulated from different clinical trials. The purpose of this review is to summarize recent outcomes and developments in stereotactic radiation therapy for patients with early stage NSCLC.

Proteomic analysis of radiation-induced changes in rat lung: Modulation by the superoxide dismutase mimetic MnTE-2-PyP(5+).

PURPOSE: To identify temporal changes in protein expression in the irradiated rat lung and generate putative mechanisms underlying the radioprotective effect of the manganese superoxide dismutase mimetic MnTE-2-PyP(5+). METHODS AND MATERIALS: Female Fischer 344 rats were irradiated to the right hemithorax with a single dose of 28 Gy and killed from day 1 to 20 weeks after irradiation. Proteomic profiling was performed to identify proteins that underwent significant changes in abundance. Some irradiated rats were administered MnTE-2-PyP(5+) and changes in protein expression and phosphorylation determined at 6 weeks after irradiation. RESULTS: Radiation induced a biphasic stress response in the lung, as shown by the induction of heme oxygenase 1 at 1-3 days and at 6-8 weeks after irradiation. At 6-8 weeks after irradiation, the down-regulation of proteins involved in cytoskeletal architecture (filamin A and talin), antioxidant defense (biliverdin reductase and peroxiredoxin II), and cell signaling (ß-catenin, annexin II, and Rho-guanosine diphosphate dissociation inhibitor) was observed. Treatment with MnTE-2-PyP(5+) partially prevented the apparent degradation of filamin and talin, reduced the level of cleaved caspases 3 and 9, and promoted Akt phosphorylation as well as ß-catenin expression. CONCLUSION: A significant down-regulation of proteins and an increase in protein markers of apoptosis were observed at the onset of lung injury in the irradiated rat lung. Treatment with MnTE-2-PyP(5+), which has been demonstrated to reduce lung injury from radiation, reduced apparent protein degradation and apoptosis indicators, suggesting that preservation of lung structural integrity and prevention of cell loss may underlie the radioprotective effect of this compound.

Bone marrow-sparing intensity-modulated radiotherapy (IMRT) for neo-adjuvant therapy of inoperable cervical cancer in a patient with severe thrombocytopenia.

BACKGROUND: Therapy possibilities are limited in patients with cervix carcinoma and thrombocytopenia. CASE REPORT: We describe a 50-year-old woman with inoperable cervical carcinoma and chronic lymphatic B cell leukemia (B-CLL). Due to thrombocytopenia, a combined radiochemotherapy could not be performed. Intensitymodulated radiotherapy (IMRT) aiming at maximal bone sparing was planned. After a total dose of 45 Gy, a laparoscopic omentum plastic was performed to enable radiotherapy (RT) to full dose. 3 days later, an external beam boost was restarted to a cumulative dose of 50.4 Gy. Regular blood analysis showed low but stable blood counts. 4 weeks after RT, magnetic resonance imaging (MRI) showed a 30% regression of the tumor volume and, after transfusion of fresh-frozen plasma, a hysterectomy could be performed. 6 months after therapy, no recurrence or late toxicities had occurred. CONCLUSION: The clinical implementation of IMRT may potentially improve the therapeutic outcome of patients with cervix cancer, allowing dose escalation without increasing normal-tissue toxicity.

Early and late administration of MnTE-2-PyP5+ in mitigation and treatment of radiation-induced lung damage.

Chronic production of reactive oxygen and nitrogen species is an underlying mechanism of irradiation (IR)-induced lung injury. The purpose of this study was to determine the optimum time of delivery of an antioxidant and redox-modulating Mn porphyrin, MnTE-2-PyP(5+), to mitigate and/or treat IR-induced lung damage. Female Fischer-344 rats were irradiated to their right hemithorax (28 Gy). Irradiated animals were treated with PBS or MnTE-2-PyP(5+) (6 mg /kg/24 h) delivered for 2 weeks by sc-implanted osmotic pumps (beginning after 2, 6, 12, 24, or 72 h or 8 weeks). Animals were sacrificed 10 weeks post-IR. Endpoints were body weight, breathing frequency, histopathology, and immunohistochemistry (8-OHdG, ED-1, TGF-beta, HIF-1alpha, VEGF A). A significant radioprotective effect on functional injury, measured by breathing frequency, was observed for all animals treated with MnTE-2-PyP(5+). Treatment with MnTE-2-PyP(5+) starting 2, 6, and 12 h but not after 24 or 72 h resulted in a significant decrease in immunostaining for 8-OHdG, HIF-1alpha, TGF-beta, and VEGF A. A significant decrease in HIF-1alpha, TGF-beta, and VEGF A, as well as an overall reduction in lung damage (histopathology), was observed in animals beginning treatment at the time of fully developed lung injury (8 weeks post-IR). The catalytic manganese porphyrin antioxidant and modulator of redox-based signaling pathways MnTE-2-PyP(5+) mitigates radiation-induced lung injury when given within the first 12 h after IR. More importantly, this is the first study to demonstrate that MnTE-2-PyP(5+) can reverse overall lung damage when started at the time of established lung injury 8 weeks post-IR. The radioprotective effects are presumably mediated through its ability both to suppress oxidative stress and to decrease activation of key transcription factors and proangiogenic and profibrogenic cytokines.

Acute neurocognitive impairment during cranial radiation therapy in patients with intracranial tumors.

BACKGROUND AND PURPOSE: The objective of the current study was to evaluate the acute effects of cranial radiation therapy (CNS-RT) using different radiation doses (0, 1.8, 2, 3, >or=20 Gy) on cognitive function with special emphasis on memory. We assessed patients with and without intracranial tumors to distinguish between direct and indirect radiation effects on brain tissue. MATERIALS AND METHODS: Eighty-two patients were evaluated with neuropsychological testing before and acutely after radiotherapy (RT). Sixty-four patients received RT to the brain (55 with, 9 without intracranial tumor). Eighteen patients treated with RT to the breast served as controls. RESULTS: Patients with intracranial tumor demonstrated attention (19-38th percentile) and verbal memory scores (34-46th percentile) below the population average at baseline. The average Verbal Memory score was significantly different between patients with intracranial tumor and controls both at baseline (38th vs. 58th percentile) and after irradiation (27th vs. 52th percentile). Patients with preexisting peritumoral edema performed worse than patients without edema and controls. Radiation dose-related deficits were seen for working memory performance in patients with intracranial tumor. CONCLUSION: Our data indicate no measurable impairment of cognitive functioning acutely after prophylactic cranial irradiation. Patients with intracranial tumor show a deterioration of almost all memory functions with a dose-dependent impairment in working memory. Patients with preexisting peritumoral brain edema show the strongest deterioration.

Memory function before and after whole brain radiotherapy in patients with and without brain metastases.

PURPOSE: To prospectively compare the effect of prophylactic and therapeutic whole brain radiotherapy (WBRT) on memory function in patients with and without brain metastases. METHODS AND MATERIALS: Adult patients with and without brain metastases (n = 44) were prospectively evaluated with serial cognitive testing, before RT (T0), after starting RT (T1), at the end of RT (T2), and 6-8 weeks (T3) after RT completion. Data were obtained from small-cell lung cancer patients treated with prophylactic cranial irradiation, patients with brain metastases treated with therapeutic cranial irradiation (TCI), and breast cancer patients treated with RT to the breast. RESULTS: Before therapy, prophylactic cranial irradiation patients performed worse than TCI patients or than controls on most test scores. During and after WBRT, verbal memory function was influenced by pretreatment cognitive status (p < 0.001) and to a lesser extent by WBRT. Acute (T1) radiation effects on verbal memory function were only observed in TCI patients (p = 0.031). Subacute (T3) radiation effects on verbal memory function were observed in both TCI and prophylactic cranial irradiation patients (p = 0.006). These effects were more pronounced in patients with above-average performance at baseline. Visual memory and attention were not influenced by WBRT. CONCLUSIONS: The results of our study have shown that WBRT causes cognitive dysfunction immediately after the beginning of RT in patients with brain metastases only. At 6-8 weeks after the end of WBRT, cognitive dysfunction was seen in patients with and without brain metastases. Because cognitive dysfunction after WBRT is restricted to verbal memory, patients should not avoid WBRT because of a fear of neurocognitive side effects.

MDR1 gene transfer using a lentiviral SIN vector confers radioprotection to human CD34+ hematopoietic progenitor cells.

Tumor radiotherapy with large-field irradiation results in an increase in apoptosis of the radiosensitive hematopoietic stem cells (CD34(+)). The aim of this study was to demonstrate the radioprotective potential of MDR1 overexpression in human CD34(+) cells using a lentiviral self-inactivating vector. Transduced human undifferentiated CD34(+) cells were irradiated with 0-8 Gy and held in liquid culture under myeloid-specific maturation conditions. After 12 days, MDR1 expression was determined by the rhodamine efflux assay. The proportion of MDR1-positive cells in cells from four human donors increased with increasing radiation dose (up to a 14-fold increase at 8 Gy). Determination of expression of myeloid-specific surface marker proteins revealed that myeloid differentiation was not affected by transduction and MDR1 overexpression. Irradiation after myeloid differentiation also led to an increase of MDR1-positive cells with escalating radiation doses (e.g. 12.5-16% from 0-8 Gy). Most importantly, fractionated irradiation (3 x 2 Gy; 24-h intervals) of MDR1-transduced CD34(+) cells resulted in an increase in MDR1-positive cells (e.g. 3-8% from 0-3 x 2 Gy). Our results clearly support a radioprotective effect of lentiviral MDR1 overexpression in human CD34(+) cells. Thus enhancing repopulation by surviving stem cells may increase the radiation tolerance of the hematopoietic system, which will contribute to widening the therapeutic index in radiotherapy.

Comparison of two Mn porphyrin-based mimics of superoxide dismutase in pulmonary radioprotection.

Development of radiation therapy (RT)-induced lung injury is associated with chronic production of reactive oxygen and nitrogen species (ROS/RNS). MnTE-2-PyP5+ is a catalytic Mn porphyrin mimic of SOD, already shown to protect lungs from RT-induced injury by scavenging ROS/RNS. The purpose of this study was to compare MnTE-2-PyP5+ with a newly introduced analogue MnTnHex-2-PyP5+, which is expected to be a more effective radioprotector due to its lipophilic properties. This study shows that Fischer rats which were irradiated to their right hemithorax (28 Gy) have less pulmonary injury as measured using breathing frequencies when treated with daily subcutaneous injections of MnTE-2-PyP5+ (3 and 6 mg/kg) or MnTnHex-2-PyP5+ (0.3, 0.6, or 1.0 mg/kg) for 2 weeks after RT. However, at 16 weeks post-RT, only MnTE-2-PyP5+ at a dose of 6 mg/kg is able to ameliorate oxidative damage, block activation of HIF-1alpha and TGF-beta, and impair upregulation of CA-IX and VEGF. MnTnHex-2-PyP5+ at a dose of 0.3 mg/kg is effective only in reducing RT-induced TGF-beta and CA-IX expression. Significant loss of body weight was observed in animals receiving MnTnHex-2-PyP5+ (0.3 and 0.6 mg/kg). MnTnHex-2-PyP5+ has the ability to dissolve lipid membranes, causing local irritation/necrosis at injection sites if given at doses of 1 mg/kg or higher. In conclusion, both compounds show an ability to ameliorate lung damage as measured using breathing frequencies and histopathologic evaluation. However, MnTE-2-PyP5+ at 6 mg/kg proved to be more effective in reducing expression of key molecular factors known to play an important role in radiation-induced lung injury.

Temporal onset of hypoxia and oxidative stress after pulmonary irradiation.

PURPOSE: To investigate the temporal onset of hypoxia following irradiation, and to show how it relates to pulmonary vascular damage, macrophage accumulation, and the production of reactive oxygen species and cytokines. Our previous studies showed that tissue hypoxia in the lung after irradiation contributed to radiation-induced injury. METHODS AND MATERIALS: Female Fisher 344 rats were irradiated to the right hemithorax with a single dose of 28 Gy. Serial studies were performed up to 20 weeks following irradiation. Radionuclide lung-perfusion studies were performed to detect changes in pulmonary vasculature. Immunohistochemical studies were conducted to study macrophages, tissue hypoxia (carbonic anhydrase-9 marker), oxidative stress (8-hydroxy-2'-deoxyguanosine), and the expression of profibrogenic (transforming growth factor-beta [TGF-beta]) and proangiogenic (vascular endothelial growth factor [VEGF]) cytokines. RESULTS: Significant changes in lung perfusion along with tissue hypoxia were observed 3 days after irradiation. Significant oxidative stress was detected 1 week after radiation, whereas macrophages started to accumulate at 4 weeks. A significant increase in TGF-beta expression was seen within 1 day after radiation, and for VEGF at 2 weeks after radiation. Levels of hypoxia, oxidative stress, and both cytokines continued to rise with time after irradiation. The steepest increase correlated with vast macrophage accumulation. CONCLUSIONS: Early changes in lung perfusion, among other factors initiate, the development of hypoxia and chronic oxidative stress after irradiation. Tissue hypoxia is associated with a significant increase in the activation of macrophages and their continuous production of reactive oxygen species, stimulating the production of fibrogenic and angiogenic cytokines, and maintaining the development of chronic radiation-induced lung injury.

Using biological markers to predict risk of radiation injury.

Recent advances in our understanding of the molecular events leading to the development of normal tissue complications after radiotherapy has led to an effort to identify biological markers that could identify patients at increased or decreased risk for treatment related injury. The goal of this effort is to improve the therapeutic ratio and enable physicians to optimize therapy for individual patients. In radiotherapy of the thoracic region, the lung is one of the most critical dose-limiting organs. This review briefly introduces the mechanisms of radiation-induced lung injury and gives a summary of clinical research focused on evaluating changes in biological markers before, during, and after radiation therapy of the thorax.

Overexpression of MDR1 using a retroviral vector differentially regulates genes involved in detoxification and apoptosis and confers radioprotection.

Overexpression of P-glycoprotein (P-gp), the product of the MDR1 (multidrug resistance 1) gene, might complement chemotherapy and radiotherapy in the treatment of tumors. However, for safety and mechanistic reasons, it is important to know whether MDR1 overexpression influences the expression of other genes. Therefore, we analyzed differential gene expression in cells of the human lymphoblast cell line TK6 retrovirally transduced with MDR1 using the GeneChip Human Genome U133 Plus2.0 (Affymetrix). Sixty-one annotated genes showed a significant change in expression (P < 10(-4)) in MDR1-overexpressing cells compared to untransduced cells and cells transduced with a control virus expressing the neomycin phosphotransferase gene. Several genes coding for proteins involved in detoxification and exocytosis showed approximately 1.4- 4-fold increases in transcript levels (e.g. ALDH1A, UNC13). Additionally, pro-apoptosis genes were down-regulated (e.g. twofold for CASP1, 2.5-fold for NALP7) with concomitant increased expression of the potential anti-apoptosis gene AKT3. In functional assays the influence of MDR1 overexpression on apoptosis signaling was further corroborated by showing reduced rates of apoptosis in response to irradiation in TK6 cells transduced with MDR1. In conclusion, the resistant phenotype of MDR1-mediated P-gp-overexpressing cells is associated with differential expression of genes coding for metabolic and apoptosis-related proteins. These results have important implications for understanding the mechanisms by which MDR1 gene therapy can protect normal tissues from radiation- or chemotherapy-induced damage during tumor treatment.

Long-term toxicity of an intraoperative radiotherapy boost using low energy X-rays during breast-conserving surgery.

PURPOSE: Intraoperative radiotherapy (IORT) as a boost for breast cancer delivers a high single dose of radiation to a late-reacting tissue; therefore late toxicity is of particular interest, and long-term follow-up is warranted. To date there are only limited data available on breast cancer patients treated with IORT using low energy X-rays. We analyzed toxicity and cosmesis after IORT as a boost with a minimum follow-up of 18 months. METHODS AND MATERIALS: A total of 73 patients treated with IORT (20 Gy/50 kV X-rays; INTRABEAM [Carl Zeiss Surgical, Oberkochen, Germany]) to the tumor bed during breast-conserving surgery as a boost followed by whole-breast radiotherapy (WBRT, 46 Gy) underwent a prospective, predefined follow-up (median, 25 months; range 18-44 months), including clinical examination and breast ultrasound at 6-months and mammographies at 1-year intervals. Toxicities were documented using the common toxicity criteria (CTC)/European Organization for Research and Treatment of Cancer and the LENT-SOMA score. Cosmesis was evaluated with a score from 1 to 4. RESULTS: The IORT in combination with WBRT was well tolerated, with no Grade 3 or 4 skin toxicities and no telangiectasias. Fibrosis of the entire breast was observed in 5% of the patients. A circumscribed fibrosis around the tumor bed was palpable in up to 27% with a peak around 18 months after therapy and a decline thereafter. The observed toxicitiy rates were not influenced by age, tumor stage, or systemic therapy. The cosmetic outcome was good to excellent in>or=90% of cases. CONCLUSIONS: After IORT of the breast using low-energy X-rays, no unexpected toxicity rates were observed during long-term-follow-up.

[Antitumoral action of interferons and interleukins in combination with radiotherapy. Part II: radiobiological and immunologic strategies]. / Antitumorale Wirkung von Interferonen und Interleukinen in Kombination mit StrahlentherapieTeil II: Strahlenbiologische und immunologische Strategien.

BACKGROUND: Combined tumor treatment with cytokines, e. g., interferons (IFN), and radiotherapy was initially of phenomenological nature but has increasingly been based on a radiobiological rationale. However, an improved understanding of the complex interactions of the cytokine network within the immune system warrants the rationale for such studies to be reviewed. METHODS: Based on published clinical studies, the results of treatment with interferons in combination with radiotherapy are reviewed. New strategies for antitumoral application of cytokines, illustrated by interleukin-(IL-)2 and IL-12 in preclinical and clinical studies, are presented. RESULTS: The initially high expectations regarding the antitumoral action of IFN-alpha, IFN-beta and IFN-gamma in combination with radiotherapy have, with few exceptions, not been fulfilled. In particular, toxicity has been a problem after systemic application. Recent advances in immunology, however, have emphasized the importance of local interactions between antigen-presenting cells and effector cells such as natural killer (NK) cells and cytotoxic T-lymphocytes in the immune reaction against tumors. Preclinical studies with IL-2 und IL-12 have shown efficacy mainly against early metastases, but immune reactions against primary tumors have also been observed. Furthermore, the method and timing of the application have proven to be critical. CONCLUSION: A few positive clinical studies give cause for hope that a therapeutic benefit may be achieved by targeted, local application of cytokines. Recent preclinical studies indicate the importance of cellular cytokine production in the interaction between the components of the immune system. Gene therapy might contribute to reduce the toxicity associated with cytokine treatment.

Prognostic factors for brain metastases after whole brain radiotherapy. Data from a single institution.

PURPOSE: Prognostic factors for overall survival of patients treated for brain metastases with whole brain radiotherapy (WBRT) at a single institution were retrospectively evaluated, and the validity of the RTOG recursive partitioning analysis (RPA) for prognostic classes was assessed. PATIENTS AND METHODS: The data of all patients (n = 268) with brain metastases from solid tumors homogeneously treated between 01/1997 and 09/1999 at the University of Heidelberg, Germany, with WBRT without surgery or radiosurgery were reviewed. 13 different patient- and therapy-related variables were evaluated for prognosis. Second, a grouping of the study cohort was performed according to the RTOG RPA prognostic classes. RESULTS: Median survival of the whole population after the start of WBRT was 3.8 months. The 1-year survival rate was 19%. Multivariate analysis revealed that only the Karnofsky performance status, control of the primary and no extracranial disease were independent prognostic factors for overall survival. These are also the main determinants of the RTOG RPA classes. Applying the RTOG RPA classes to the authors' data set revealed three subgroups with significantly different prognosis. CONCLUSION: Based on this analysis, prognostic factors for survival after WBRT in patients with brain metastases could be identified. A total of 19% (n = 44/232) survived > or = 1 year, whereas overall survival was poor. The potential value of the RPA classes in estimating the patient's prognosis could be confirmed.

[Antitumoral action of interferons and interleukins in combination with radiotherapy. Part I: immunologic basis]. / Antitumorale Wirkung von Interferonen und Interleukinen in Kombination mit Strahlentherapie. Teil I: Immunologische Grundlagen.

BACKGROUND: During the last 2 decades, cytokines such as interferons (IFN) have been used to modulate tumor response in radiotherapy. Initially, the focus was on antiviral and radiosensitizing effects of interferons but increasingly, the function of interferons and interleukins (IL) within the immune response to tumor cells is becoming important. METHOD: The cellular immune response toward tumor cells is reviewed. The role of cytokines in antigen presentation and activation of effector cells and their interactions with radiation are described. Preclinical strategies of the antitumor action of cytokines are presented and discussed based on the induction of IFN-gamma by IL-12. RESULTS: Recent advances in immunology have demonstrated the importance of local interactions between antigen-presenting cells (APC) and effector cells such as natural killer (NK) cells and T-lymphocytes for an effective immune reaction against tumors. Interferons stimulate such interactions, while IL-2 plays a central role in the activation of NK cells and T-lymphocytes. The interactions between APC and effector cells are suppressed by many tumors but can be stimulated by irradiation. Since systemic application of interferons is quite toxic, present strategies aim at local expression, e. g., the induction of IFN-gamma expression in Th1 cells by IL-12. CONCLUSION: The improved understanding of immunologic mechanisms has emphasized the role of the cytokine network in the interaction between tumor cells and effector cells such as NK cells and T-lymphocytes. This opens new possibilities for the application of cytokines as biological response modifiers, which may eventually help widening the therapeutic window in radiotherapy.

Irradiation for conjunctival granulocytic sarcoma.

CASE HISTORY AND FINDINGS: A 73-year-old woman with a history of myeloproliferative syndrome (MPS) presented with bilateral chemosis, redness and burning of the eyes. The ocular motility was severely impaired. Ophthalmological examination revealed markedly distended conjunctivas on both sides. Biopsy disclosed conjunctival granulocytic sarcoma as an initial symptom of acute myelogenous leukemia (AML). Diagnosis was confirmed by peripheral blood smear and bone marrow aspiration. TREATMENT AND OUTCOME: The orbital tumor disappeared completely after local external beam irradiation with a total dose of 30 Gy and no further orbital recurrence occurred. With chemotherapy following irradiation transient hematological remission was achieved. 5 months after diagnosis the patient died of respiratory failure following atypical pneumonia as a consequence of her underlying disorder. CONCLUSION: Detection of orbital granulocytic sarcoma, even in the absence of typical leukemic symptoms is of practical importance, because treatment with irradiation can lead to stabilization or improvement in the patient's vision.