Treatment of telangiectasias with a 595-nm pulsed dye laser following hemangioma involution: a retrospective analysis.

Telangiectasias are the most frequent type of sequelae of infantile hemangiomas after involution. Few studies have reported the treatment of telangiectasias with 595-nm pulsed dye lasers. Therefore, the objective of this study was to assess the efficacy and safety of a 595-nm pulsed dye laser for treating residual telangiectasias following hemangioma involution. This is a retrospective case series that analyzes the medical records and reviews the charts of 22 patients who had undergone 595-nm pulsed dye laser treatment for residual telangiectasias. Pre- and post-treatment digital images were independently assessed, and the changes were scored to ascertain the efficacy of the treatment (0 = no change, 4 = complete improvement). Of the 22 patients, 59.1% experienced complete resolution of telangiectasias following treatment. No serious complications or side effects were reported. The observations indicate that the 595-nm pulsed dye laser is effective and safe for treating residual telangiectasias following hemangioma involution.

Could a low-dose definitive radiation therapy be the optimal treatment for choroidal hemangioma?

PURPOSE: To determine the efficacy of low-dose intensity-modulated radiation therapy (IMRT)/volumetric intensity-modulated arc therapy (VMAT) in the treatment of symptomatic choroidal hemangioma (CH). MATERIALS AND METHODS: Fifty-three consecutive patients with CH were retrospectively reviewed. All the patients underwent IMRT/VMAT as a unique treatment. Resolution of subretinal fluid (SRF), improvement of best-corrected visual acuity (BCVA), and reduction in tumor thickness were compared before and after radiotherapy. RESULTS: After definitive radiotherapy, 100 % of SRF and 76.7 % of exudative retinal detachment were resolved. 56.6 % of BCVA improvement in more than two lines was observed. The mean best-corrected visual acuity was 20/280 (range, 20/1200-20/40) at diagnosis and 20/100 (range, 20/1200-20/20) after treatment. The mean tumor thickness decreased significantly from 3.8 mm initially to 1.2 mm after treatment (p < 0.01). 66.0 % of patients were delivered with 21.6 Gy (range, 21.6-42 Gy), 84.9 % of fractional dose was 1.8 Gy (range, 1.8-2 Gy). No radiation-induced keratitis, retinopathy, or optic neuropathy were observed. Initial vision (p = 0.042), duration time of vision (p = 0.004), and tumor thickness (p = 0.049) were prognostic factors for vision recovery. CONCLUSION: Low-dose IMRT/VMAT could effectively induce involution of the CH, with reduction of subretinal fluid and relief of damage to the neurosensory retina, which is an effective treatment mode for CH.

Scientific validation of clinical visual scales and Antera 3D™ consistency with derived measurements in the assessment of infantile haemangioma after laser therapy.

BACKGROUND: Laser therapy is a treatment for infantile haemangiomas. The efficacy of laser therapy for red lesions is determined by visual evaluation; however, this assessment is inaccurate and lacks objectivity. OBJECTIVE: To scientifically validate the consistency between pre- and post-treatment visual assessment grades for infantile haemangioma treated with pulsed dye laser (PDL) and the values calculated from images obtained with Antera 3D™. METHODS: This study involved 81 cases of infantile haemangiomas treated with PDL alone from 2012 to 2015 and with Antera 3D™ images of the lesions. Using images obtained before treatment and 4-6 weeks after the last treatment, the lesions were rated using a visual four-step scale. Ratings were categorised as Poor/Fair/Good/Excellent by the degree of improvement in the red colour tone. The red colour ratio was calculated using the haemoglobin distribution in the lesion and surrounding skin, and the improvement difference and improvement rate were then obtained. The correlation between the improvement difference and improvement rate, and visual evaluation was statistically analysed. RESULTS: No serious adverse effects were observed, with an average of 4.3 treatments per patient; 60.1% of the patients achieved Good/Excellent results. There were statistically significant differences in the post-treatment red colour ratio and improvement ratio in each category after visual evaluation classification. The improvement rate and the four visual grades were statistically correlated. CONCLUSION: This study confirmed the scientific validity of visual evaluation and the evaluation criteria calculated from Antera 3D™. This method could objectively determine treatment effectiveness.

Revealing the mechanism of 755-nm long-pulsed alexandrite laser in inhibiting infantile hemangioma endothelial cells through transcriptome sequencing.

Laser therapy has shown promising outcomes in treating infantile hemangiomas. However, the molecular mechanisms underlying laser treatment for IH remain incompletely elucidated. This study aimed to unravel the molecular mechanisms of laser therapy in IH treatment. We evaluated the inhibitory effects of laser treatment on the proliferation and promotion of apoptosis in human hemangioma endothelial cells (HemECs) through cell counting kit-8 (CCK-8) assay, Hoechst 33342 staining, and flow cytometric analysis. Transcriptome sequencing analysis of HemECs following laser treatment revealed a significant decrease in the expression level of the GSTM5 gene. The qRT-PCR and western blot analysis also showed that GSTM5 expression in HemECs was downregulated compared to human umbilical vein endothelial cells (HUVECs), and concomitantly, the p62-Nrf2 pathway was suppressed. Using siRNA to downregulate GSTM5 expression, we observed that inhibiting GSTM5 expression could restrain cell proliferation, elevate intracellular ROS levels, and induce apoptosis in HemECs. Furthermore, upon inhibition of the p62-Nrf2 pathway using p62-specific siRNA, a significant decrease in GSTM5 expression and an elevation in intracellular ROS levels were noted in laser-treated HemECs. These findings suggested that laser treatment may operate by inhibiting the p62-Nrf2 pathway, thereby downregulating GSTM5 expression, elevating ROS levels, and consequently inducing apoptosis in HemECs.

Basal cell carcinoma arising at the site of a previously irradiated infantile hemangioma.

We describe a case of a previously irradiated infantile hemangioma in a patient 1 year of age. At the age of 78, the patient presented with a pink, pearly plaque at the previously irradiated infantile hemangioma site and was found to have a nodular basal cell carcinoma. [Correction added on 30 August 2023, after first online publication: In the preceding sentence, patient age has been corrected in this version] This case highlights the rare, but long-term risks of radiation therapy for hemangiomas, but also presents an interesting historical vignette in dermatological treatments, with photographic documentation. It also represents the longest time interval between irradiation of an infantile hemangioma and the development of a basal cell skin cancer, 70 years in this case.

IODINE-125 PLAQUE BRACHYTHERAPY FOR DIFFUSE CHOROIDAL HEMANGIOMA.

PURPOSE: To report 6 cases of diffuse choroidal hemangioma in children treated with iodine-125 plaque brachytherapy at a single tertiary care center. METHODS: Retrospective case series. RESULTS: Six pediatric patients diagnosed with diffuse choroidal hemangioma were included in the study. Preplaque visual acuity ranged from 20/150 to no light perception. All patients had extensive serous retinal detachment at presentation. An iodine-125 radioactive plaque was placed on the affected eye to administer a dose of 34.2-42.1 Gy to the tumor apex over a median of 4 days. Tumor regression and subretinal fluid resolution were observed in all eyes within 17 months of treatment. Visual acuity improved in two patients. Radiation-induced cataract and subretinal fibrosis were documented in one case, and one patient developed radiation retinopathy. No patients developed neovascular glaucoma within the follow-up time of 12-65 months. CONCLUSION: Iodine-125 plaque radiotherapy is an effective option for diffuse choroidal hemangioma, although there is a risk for radiation-induced complications.

Assessment of the efficacy of 595 nm pulsed dye laser in the management of facial flat angiomas. Results of a case series.

BACKGROUND: Studies on pulsed dye laser (PDL) have shown the best efficacy and safety data for treating vascular anomalies among the various lasers used and the 595-nm PDL has been used to treat cutaneous vascular anomalies for about 30 years. The purpose of this study was to assess the efficacy of 595 nm Pulsed Dye Laser in the management of facial flat angiomas present in the form of Port-Wine Stain. MATERIALS AND METHODS: Seven cases of PWS in Fitzpatrick skin type ranged from I to III and colour ranging from pink to purple, were treated with 595 nm pulse Dye Laser. Patients underwent to 6-8 laser sessions at 20-30 days intervals. Results obtained were judged by dermatologist, by comparing pre-treatment and post-treatment photographs, 6 months after the last session and a quartile scale of lesion clearance (4-point Investigator Global Assessment scale): 1 = no or low results (0%-25% of the lesion area improved), 2 = slight improvement (25%-50% of the lesion area cleared), 3 = moderate-good improvement (50%-75%), and 4 = excellent improvement (75%-100%) was used. Possible side effects such as blisters, hyper/hypopigmentation, and scarring were monitored. RESULTS: All patients observed global improvements. 71% of patients achieved excellent clearance and 29% patients achieved good-moderate clearance of their angioma. Patients were asked for a subjective evaluation of the results: 57% of patients were very satisfied, 29% were satisfied, and 14% patients were not very satisfied with the results. No patients were dissatisfied. No significant side effects were noted. CONCLUSION: This research confirms the efficacy of the 595 nm PDL for flat angioma management, without considerable side effects.

How efficient is laser therapy for telangiectasias, spider veins, and cherry angiomas?-A study using dynamic optical coherence tomography.

OBJECTIVES: A clinical study to investigate the effectiveness of pulsed dye laser (PDL) versus Nd:YAG laser in the treatment of telangiectasias, spider veins and cherry angiomas. Dynamic optical coherence tomography (D-OCT) was introduced as an innovative follow-up tool for evaluation of blood flow within superficial vessels and to allow visualization of morphological changes of the vasculature in vivo. The final aim of this study was to demonstrate a possible treatment benefit comparing both laser types. MATERIALS AND METHODS: Vessel structures of 102 skin lesions were documented photographically and dermoscopically. Subsequently, lesions were imaged using optical coherence tomography before laser therapy (a), directly after the treatment (p) and after a follow-up 4-6 weeks after laser treatment. All lesions were treated using either a 595 nm PDL or a 1064 nm Nd:YAG laser. Two main vessel parameters, namely density and diameter, and their possible changes during follow-up were observed in 150/300/500 µm penetration depth using D-OCT and were subsequently compared between both treatment groups. Other analyzed vessel parameters were depth of the plexus, mean diameter, mean density, top edge of the vessel, columns, and spikes. RESULTS: Both laser types are suitable options for the treatment of vascular skin lesions, with the most significant effect on cherry angiomas. PDL shows better results treating smaller vessels in upper skin regions, in comparison to Nd:YAG laser, achieving better results on deeper vessels, like spider veins. Using the applied laser settings, there was no statistically significant effect on telangiectasias. CONCLUSION: D-OCT represents a new, noninvasive imaging method to evaluate blood flow and vessel morphology in the follow-up of telangiectasias, spider veins, and cherry angiomas, which underwent laser therapy.

Laser treatment of infantile hemangioma.

BACK GROUNDS AND OBJECTIVE: Infantile hemangiomas (IH) are common benign tumors of infancy. Most IH either involute spontaneously or respond to treatment with systemic Beta- blockers, but unfortunately not in all cases. In poor responses or in cases of contra indications for pharmacological treatment, laser treatment poses a very good solution. METHODS: As a search strategy and study selection we searched the MEDLINE database via PubMed starting 1982 to June 2022 using a key terms related to interventions for IH (e.g., infantile hemangioma, laser, Beta blockers). RESULTS: In this article, we reviewed the published data regarding the use of energy-based devices in treatment of children with IH, and noted our experience over the course of treating dozens of cases over the years. CONCLUSION: There are many laser systems used for the treatment of hemangioma and vascular tumors. These laser systems are of different wavelengths and penetration depths, however, they operate by similar mechanisms and in some cases two or more lasers can be applied during the course of treating these lesions.

Hypofractionated stereotactic radiosurgery for aggressive vertebral haemangioma and useful follow-up imaging modality: case report and review of the literature.

We report the use of an advanced magnetic resonance image (MRI) sequence to detect the treatment response after SRS for aggressive vertebral haemangioma (VH). A 63-year-old female patient presented with back pain, bilateral lower extremity weakness (grade IV), and sensory change in the saddle area. MRI revealed a vertebral body mass compressing the spinal cord at T10, which had high T2 and low T1 signal intensity. Three-dimensional volumetric sagittal time-resolved imaging of contrast kinetics (TRICKS) abdominal magnetic resonance angiography (MRA) showed it to be hypervascular. SRS with the Novalis beam shaping system (BrainLAB; Heimstetten®, Germany) was performed on the gross tumor volume of 14.954 mL. 30 Gy was given to the 90% isodose line in 5 fractions. Seven days later, the patient underwent decompressive laminectomy for weakness. Seven months later, the patient's motor weakness was improved to allow for unassisted gait, and back pain and sensory changes resolved. Follow-up MRI revealed no significant change on T1 and T2 signal intensity images. However, TRICKS abdominal MRA demonstrated disapprearance of the hypervascularity. Seven years after SRS, the same signal intensity images showed shrinkage of the mass and resolution of compression of the spinal cord, and the signal intensity of the T1 image was changed to iso- and high signal intensity.

Multicenter retrospective review of pulsed dye laser in nonulcerated infantile hemangioma.

BACKGROUND/OBJECTIVES: We sought to describe the experience among members of the Hemangioma Investigator Group with pulsed dye laser (PDL) in the treatment of nonulcerated infantile hemangioma (IH) in pediatric patients in the pre- and post-beta-blocker era. METHODS: A multicenter retrospective cohort study was conducted in patients with nonulcerated IH treated with laser therapy. Patient demographics, IH characteristics, indications for/timing of laser therapy, as well as laser parameters were collected. Responses to laser therapy were evaluated using a visual analog scale (VAS). RESULTS: One hundred and seventeen patients with IH were treated with PDL. 18/117 (15.4%) had early intervention (defined as <12 months of life), and 99/117 (84.6%) had late intervention (≥12 months of life). In the late intervention group, 73.7% (73/99) had additional medical management of their IH. The mean age at PDL initiation for the late intervention group was 46.7 ± 35.3 months of life (range 12-172 months) with total number of treatments to maximal clearing of 4.2 ± 2.8 (range 1-17). Those who received propranolol prior to PDL received fewer sessions (1.1 fewer sessions, approaching significance [p = .056]).     On the VAS, there was a mean 85% overall improvement compared to baseline (range 18%-100%), with most improvement noted in erythema and/or telangiectasias. The incidence of adverse effects was 6/99 (6.1%). CONCLUSIONS: PDL is a useful tool in the treatment of IH, with notable improvement of telangiectasia and erythema and low risk of complications.   PDL is often introduced after the maximal proliferative phase.

Conventionally fractionated radiotherapy versus CyberKnife hypofractionated radiotherapy for painful vertebral haemangiomas - A randomized clinical trial.

BACKGROUND AND PURPOSE: The outcomes of conventional radiotherapy for painful vertebral haemangiomas have been improved through dose escalation at the expense of overall treatment time. We hypothesized that with the aid of precise hypofractionated radiotherapy, it is possible to safely deliver a similar biological equivalent dose over a significantly shorter course of treatment with a comparable efficacy and safety. MATERIALS AND METHODS: In this prospective, single-institution unblinded randomized clinical trial (NCT02332408) patients with painful vertebral haemangiomas were allocated one-to-one either to 25 Gy delivered in five fractions (CK) or conventionally fractionated radiotherapy up to 36 Gy (conv.). The main endpoint was pain relief at two years, measured on a subjective and numerical scale (NRS). RESULTS: The trial was finished yielding 74 evaluable patients, including 38 in the CK arm. Adverse events were infrequent and the treatment was well tolerated. The overall treatment time was significantly shorter in the CK arm (median of 13 days vs 25 days). At two years, more than half of the patients reported improvement (46; 62.2 %) , in 21 cases the pain symptoms were stable (28.4 %), and in seven cases worse (9.5 %). There were significantly more patients reporting improvement in the CK arm (73.7 % vs 50 %; p = 0.036). The median decrease in NRS was 4 (IQR 1-5) or 59 % (IQR 20-86 %), and the difference between arms was not statistically significant. CONCLUSION: Five fractions hypofractionated radiotherapy for painful vertebral haemangiomas up to a total dose of 25 Gy is a safe treatment modality, significantly shorter compared to conventional fractionation, and possibly more effective.

Optimizing parameters of the Pulsed Dye Laser (PDL, 585-nm) for hemangioma treatment using diffuse reflectance spectroscopy.

INTRODUCTION: The lack of objectivity options for a specific individualized therapy might cause challenges in laser treatment. In other words, we need optimally determined laser parameters for less side effects. Generally, laser treatment procedures seem to be subjective. Then, the final evaluation of the patient needs for optimized better response with less laser sections and less side effects. Therefore, employing a reliable objective technique seems to be essential for better response with less laser treatment sessions and also less side effects. METHOD: In this research, UV-visible diffused reflection spectra from normal skin and a lesion were taken. We obtained the differences in absorption intensity at 575 nm, the wavelength corresponds to the absorption peak of blood oxyhemoglobin for normal skin and hemangioma. To calibrate the measurements, after using pulsed dye laser (PDL at 585 nm), the PDL treatment response of the patients were graded as "good (>50%), moderate(25%-50%), and poor (0%-25%)," by a specialist. Finally, patients were categorized based on the energy of the laser for the best treatment response to propose the recommended laser parameters. RESULTS: Based on the differences in the absorption peak hemangioma compare with normal skin, the energy density of PDL for a good treatment response of hemangioma was obtained at peak wavelength 575 nm. CONCLUSION: The analysis of optical reflection spectroscopy can assess the correlation of absorption peak differences of vascular lesions and normal skin. According to this data, it seems to be effective in optimizing lasers parameters for the hemangioma treatment.

Laser Treatment of Vascular Anomalies.

Lasers are a safe and effective tool for the treatment of vascular anomalies. There are many laser options available. Matching laser parameters with the characteristics of the vasculature in these lesions can selectively deliver energy to the abnormal tissue. This can lead to reduction in size and symptoms of vascular malformations and hemangiomas.

Clinical Outcomes of Small Infantile Hemangiomas Treated With Pulsed Dye Laser.

BACKGROUND: Infantile hemangioma (IH) often causes cosmetic disfigurement. Early intervention with propranolol for large, high-risk lesions is recommended in the American Academy of Pediatrics' Clinical Practice Guideline. Conversely, strategies for the management of small, low-risk lesions have not been established; however, pulsed dye laser (PDL) is often used to treat these lesions. OBJECTIVE: To investigate clinical outcomes of PDL in small IH lesions. PATIENTS AND METHODS: Fifty-three cases with 58 small IHs which did not meet the criteria for high-risk lesions in the guideline and were treated only with PDL were retrospectively reviewed. The characteristics of IHs and residual skin changes after treatment were evaluated. RESULTS: Forty-seven lesions (81.0%) were superficial hemangiomas, whereas 11 (19.0%) were combined-type. The median maximum diameter was 10.0 mm. Forty-five lesions (77.6%) exhibited various residual skin changes after PDL treatment, including anetoderma (53.5%), telangiectasia and erythema (43.1%), hyperpigmentation (34.5%), redundant skin (3.4%), and fibrofatty tissue (3.4%). Of these, the incidence of anetoderma and fibrofatty tissue were significantly higher in the combined group than in the superficial group ( p = .036 and .033, respectively). CONCLUSION: Even small lesions, especially combined-type, often result in cosmetic problems after PDL treatment.

Radiosurgery for Benign Vertebral Body Hemangiomas of the Spine: A Systematic Review and Meta-Analysis.

OBJECTIVE: Spinal vertebral hemangiomas (SVHs) are the most common benign tumors of the spine. We performed a systematic review and meta-analysis of radiosurgery (RS) for SVHs. METHODS: We reviewed articles published between January 1990 and December 2020 on PubMed. Tumor control, pain relief, and damage to surrounding tissues were evaluated with separate meta-analyses. This study was performed in accordance with the published Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 23 patients with 24 SVHs were reported in 3 studies. RESULTS: Follow-up time was 7.3-84 months. The vast majority of lesions were located at dorsal level (n = 18; 75%). In 20 (83.3%) patients, pain was the initial clinical presentation. Complete, partial, and stable responses after radiation were reported in 45.7% (P < 0.001), 23.6% (P = 0.02), and 37.2% (P = 0.7) of cases. Overall response was reported in 94.1% (P = 0.7). No progressive disease was reported. Pain relief was achieved in 87.5% of patients (P = 0.2). Damage to surrounding tissue caused by irradiation was reported in 22.3% (P = 0.02) of cases in 1 study, in which higher doses of radiation were delivered. CONCLUSIONS: Radiosurgery is safe and effective for SVHs. Pain relief after RS in symptomatic patients was extremely high, while no progressive disease was reported. Damage to surrounding tissues was reported in only 1 series and included osteitis, osteonecrosis, or soft tissue injury after higher radiation doses.

Radiotherapy for vertebral hemangioma: the single-center experience of 80 patients.

PURPOSE: This study aimed to evaluate the therapeutic effect of radiotherapy and to determine possible prognostic factors in patients with painful vertebral hemangioma. METHODS: In the last two decades, 80 patients with vertebral hemangioma who received radiotherapy in our institute were evaluated in terms of pain response, treatment-related side effects, and prognostic factors. All patients were questioned 3 months after radiotherapy for the evaluation of pain response and were divided into three groups (complete response, partial response, and no change). Moreover, the visual analog scale (VAS) was used for pain response assessment in 46 patients. Pain status was assessed to detect recurrence at each clinical examination during the follow-up period. Possible prognostic factors such as gender, size of the hemangioma, location, multilevel involvement and additional musculoskeletal disease on pain response were analyzed. RESULTS: In this study, 45 individuals had lesions in the lumbar spine, 28 in the thoracic, and 7 in the cervical region. Furthermore, 51 patients had additional musculoskeletal conditions such as disc herniation, degenerative diseases, spondylolisthesis, and compression fracture. Radiotherapy was performed with a median daily dose of 2 Gy and a median total dose of 40 Gy. Complete pain response occurred in 58.8% of patients, 26.2% of patients had partial pain response, and 15% of patients had no pain response. The overall response rate was 85%, and 7 patients showed recurrent pain symptoms in the overall response group at routine follow-up. Additional musculoskeletal disorders were found to be the only prognostic factor associated with pain response. The median follow-up time was 60 months. Secondary malignancy was not found in any of the patients in this short follow-up time. No acute or late radiation-associated side effects greater than grade II were observed. CONCLUSION: To our best knowledge, this study is one of the largest single-institution radiotherapy series on vertebral hemangiomas reported to date. The obtained data support the efficacy and safety of radiotherapy in the treatment of painful vertebral hemangioma. Our study showed that additional musculoskeletal disease plays an important role in pain response. Other prognostic factors and treatment of vertebral hemangioma with stereotactic radiosurgery should be investigated in future studies.

[Radiation therapy of hepatic haemangiomas: Review from a case report]. / Radiothérapie externe des angiomes hépatiques : revue de la littérature, à partir d'un cas.

Haemangioma is the most frequent benign hepatic tumour. Haemangioma is generally asymptomatic but it can sometimes cause disabling symptoms depending on its size and location. Surgery and interventional radiology are the cornerstone of the treatment in this situation. Radiation therapy, already used with good efficacy and safety to treat hepatic malignant lesions as hepatocarcinoma and metastases, is a relevant option in case of contraindication to surgery because of multiple or very large lesions. In this context, we report the case of a patient presenting with multiple symptomatic hepatic haemangiomas, successfully treated by radiation therapy in our department. These good results justified a review of the literature to report series of patients treated in this indication and to describe the main treatment regimens used.

Single-center outcomes of image-guided radiotherapy in the management of vertebral hemangioma with daily kilovoltage cone-beam computerized tomography.

BACKGROUND: Vertebral hemangiomas are defined as benign proliferation of blood vessels. Vertebral hemangiomas are generally found incidentally by computerized tomography or magnetic resonance imaging; however, they may also cause pain and quality-of-life impairment in some circumstances with reference to their location and association with the spinal cord. In this study, we assessed the utility of image-guided radiation therapy (IGRT) in the management of patients with painful vertebral hemangioma. MATERIALS AND METHODS: Patients receiving IGRT for the management of painful vertebral hemangioma were evaluated. The total dose was 24 Gy delivered in 12 daily fractions. The verbal numeric scale (VNS) was used for the assessment of pain relief. The median follow-up duration was 13 months (range: 6-24 months). RESULTS: Median preradiotherapy VNS score was 8 (range: 6-10) and median postradiotherapy VNS score was 1 (range: 0-2) for the total 135 patients treated with IGRT at our department for painful vertebral hemangioma. Reduction in VNS scores after IGRT was statistically significant (P < 0.05). CONCLUSION: Our single-center study revealed that IGRT resulted in substantial relief of pain from vertebral hemangioma. Randomized prospective multicenter trials are needed to shed light on the optimal management of patients suffering from pain due to vertebral hemangioma.