Radiotherapy and Systemic Treatment for Leptomeningeal Disease.

Leptomeningeal disease (LMD) is a devastating sequelae of metastatic spread that affects approximately 5% of cancer patients. The incidence of LMD is increasing due to advancements in systemic therapy and enhanced detection methods. The purpose of this review is to provide a detailed overview of the evidence in the detection, prognostication, and treatment of LMD. A comprehensive literature search of PUBMED was conducted to identify articles reporting on LMD including existing data and ongoing clinical trials. We found a wide array of treatment options available for LMD including chemotherapy, targeted agents, and immunotherapy as well as several choices for radiotherapy including whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and craniospinal irradiation (CSI). Despite treatment, the prognosis for patients with LMD is dismal, typically 2-4 months on average. Novel therapies and combination approaches are actively under investigation with the aim of improving outcomes and quality of life for patients with LMD. Recent prospective data on the use of proton CSI for patients with LMD have demonstrated its potential survival benefit with follow-up investigations underway. There is a need for validated metrics to predict prognosis and improve patient selection for patients with LMD in order to optimize treatment approaches.

Proton versus photon craniospinal irradiation for adult medulloblastoma: A dosimetric, toxicity, and exploratory cost analysis.

Background: This study aimed to determine whether proton craniospinal irradiation (CSI) decreased the dose to normal tissue and resulted in less toxicity than photon CSI for adult patients. Methods: This single-institution retrospective analyzed differences in radiation doses, acute toxicity, and cost between proton and CSI for adult medulloblastoma patients. Results: Of 39 total patients, 20 were treated with photon CSI prior to 2015, and 19 were treated with proton CSI thereafter. Median age was 28 years (range 18-66). The molecular subtype was most commonly sonic hedgehog (68%). Patients most commonly received 36 Gy CSI in 20 fractions with a boost to 54-55.8 Gy (92%). Proton CSI delivered significantly lower mean doses to cochleae, lacrimal glands, lens, parotid glands, pharyngeal constrictors, esophagus, lungs, liver, and skin (all P < .001). Patients receiving proton CSI had significantly lower rates of acute dysphagia of any grade (5% versus 35%, P = .044) and decreased median weight loss during radiation (+1.0 versus -2.8 kg, P = .011). Weight loss was associated with acute hospitalization (P = .009). Median follow-up was 2.9 and 12.9 years for proton and photon patients, respectively, limiting late toxicity and outcome comparisons. At the last follow-up, 5 photon patients had died (2 of progressive disease, 3 without recurrence ages 41-63) and 21% had experienced major cardiovascular events. At 10 years, 89% were alive and 82% were recurrence free. Conclusions: This study demonstrates dosimetric improvements with proton CSI, potentially leading to decreased acute toxicity including dysphagia and weight loss during treatment.

Spinal Meningeal Mass Lesion: A Rare Presentation of Primary Dural Follicular Lymphoma.

INTRODUCTION: The differential diagnosis of a spinal intradural extramedullary mass lesion is broad and includes meningioma, schwannoma, neurofibroma, leptomeningeal metastasis, and myxopapillary ependymoma. Though rare, lymphoma should be included in the differential diagnosis of a dural mass lesion. CASE REPORT: A 38-year-old man presented with back pain that progressed over 1 month with associated focal tenderness over his mid to lower thoracic spine. He developed intermittent numbness of the bilateral lower extremities, nuchal rigidity, difficulty sleeping, and night sweats. A magnetic resonance imaging of the thoracic spine demonstrated a dorsal intradural extramedullary enhancing lesion from T7 to T10 extending outside the spinal canal. Dural thickening across the entire circumference of the spinal cord was noted. Computed tomography (CT)-guided biopsy of the thoracic lesion was performed, and pathology was consistent with follicular lymphoma. Fluorodeoxyglucose positron emission tomography:CT demonstrated no systemic disease. Bone marrow biopsy was negative for malignancy. Symptoms resolved with dexamethasone therapy. He was treated with bendamustine and rituximab with follow-up positron emission tomography:CT 2 months later demonstrating a complete response. CONCLUSIONS: Lymphoma can rarely present as an isolated dural lesion and should be considered in the differential diagnosis of intradural extramedullary spinal mass lesions. Prompt diagnosis and initiation of treatment can lead to complete response and resolution of symptoms.

Withdrawal of bevacizumab is associated with rebound growth of vestibular schwannomas in neurofibromatosis type 2-related schwannomatosis patients.

Background: Neurofibromatosis type 2 (NF2)-related schwannomatosis is an autosomal dominant tumor-predisposition syndrome characterized by bilateral vestibular schwannomas (VS). In patients with VS associated with NF2, vascular endothelial growth factor A inhibitor, bevacizumab, is a systemic treatment option. The aim of this study is to retrospectively evaluate NF2 patient responses to bevacizumab on VS growth and symptom progression. Methods: This is a retrospective analysis of patients seen at the Mayo Clinic Rochester Multidisciplinary NF2 Clinic. Results: Out of 76 patients with NF2 evaluated between 2020 and 2022, we identified 19 that received treatment with bevacizumab. Thirteen of these patients discontinued bevacizumab after median treatment duration of 12.2 months. The remaining 6 patients are currently receiving bevacizumab treatment for a median duration of 9.4 months as of March, 2023. Fifteen patients had evaluable brain MRI data, which demonstrated partial responses in 5 patients, stable disease in 8, and progression in 2. Within 6 months of bevacizumab discontinuation, 5 patients had rebound growth of their VS greater than 20% from their previous tumor volume, while 3 did not. Three patients with rebound growth went on to have surgery or irradiation for VS management. Conclusions: Our single-institution experience confirms prior studies that bevacizumab can control progression of VS and symptoms associated with VS growth. However, we note that there is the potential for rapid VS growth following bevacizumab discontinuation, for which we propose heightened surveillance imaging and symptom monitoring for at least 6 months upon stopping anti-VEGF therapy.

The Current Status, Challenges, and Future Potential of Therapeutic Vaccination in Glioblastoma.

Glioblastoma (GBM) is the most common malignant primary brain tumor and confers a dismal prognosis. With only two FDA-approved therapeutics showing modest survival gains since 2005, there is a great need for the development of other disease-targeted therapies. Due, in part, to the profound immunosuppressive microenvironment seen in GBMs, there has been a broad interest in immunotherapy. In both GBMs and other cancers, therapeutic vaccines have generally yielded limited efficacy, despite their theoretical basis. However, recent results from the DCVax-L trial provide some promise for vaccine therapy in GBMs. There is also the potential that future combination therapies with vaccines and adjuvant immunomodulating agents may greatly enhance antitumor immune responses. Clinicians must remain open to novel therapeutic strategies, such as vaccinations, and carefully await the results of ongoing and future trials. In this review of GBM management, the promise and challenges of immunotherapy with a focus on therapeutic vaccinations are discussed. Additionally, adjuvant therapies, logistical considerations, and future directions are discussed.

Leptomeningeal anti-tumor immunity follows unique signaling principles.

Metastasis to the cerebrospinal fluid (CSF)-filled leptomeninges, or leptomeningeal metastasis (LM), represents a fatal complication of cancer. Proteomic and transcriptomic analyses of human CSF reveal a substantial inflammatory infiltrate in LM. We find the solute and immune composition of CSF in the setting of LM changes dramatically, with notable enrichment in IFN-γ signaling. To investigate the mechanistic relationships between immune cell signaling and cancer cells within the leptomeninges, we developed syngeneic lung, breast, and melanoma LM mouse models. Here we show that transgenic host mice, lacking IFN-γ or its receptor, fail to control LM growth. Overexpression of Ifng through a targeted AAV system controls cancer cell growth independent of adaptive immunity. Instead, leptomeningeal IFN-γ actively recruits and activates peripheral myeloid cells, generating a diverse spectrum of dendritic cell subsets. These migratory, CCR7+ dendritic cells orchestrate the influx, proliferation, and cytotoxic action of natural killer cells to control cancer cell growth in the leptomeninges. This work uncovers leptomeningeal-specific IFN-γ signaling and suggests a novel immune-therapeutic approach against tumors within this space.

Agenesis of the Corpus Callosum and Generalized Epilepsy.

The corpus callosum is the main band of interhemispheric axonal fibers in the human brain. Corpus callosum agenesis has widely varying symptoms, mainly associated with epilepsy, cognitive failure, and different neuropsychiatric disorders. Our case of corpus callosum agenesis includes eyelid myoclonia with absences. In the literature, there is no reported case of this combination. We report this case because it is rare, and relevant for the understanding of interhemispheric communications, based on our electrophysiological findings.

The association of biomass fuel combustion on pulmonary function tests in the adult population of Mid-Anatolia.

OBJECTIVES: To assess the association of biomass as domestic energy source on respiratory function in rural areas of Mid-Anatolia in Turkey where biomass use is frequent. METHODS: In a cross-sectional study, pulmonary functions measurements of 112 cow-dung users and 153 modern energy source users, all non-smokers, were assessed and compared. Several sociodemographic factors were assessed by questionnaire, and ventilatory function measurements included forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio and the flow between the first 25 and 75 of forced expiratory flow (FEF(25-75)), and were compared, deploying univariate and multivariate methods, between the two groups. RESULTS: The individuals in the biomass exposed and unexposed group were similar regarding demographic characteristics: 67.0% were female (exposed) vs 60.1% (unexposed) with an age range of 17 to 64 (exposed) and 18 to 70 years (unexposed), and with 36% of biomass users having had pulmonary tract infections (20% in non-users). For all pulmonary function test parameters FEV1, FVC, FEV1/FVC, and FEF(25-75) a highly significant (p < 0.0001) reduction was observed in biomass users. A 12.4% (95% confidence interval: 7.0% to 17.7%) reduction in forced vital capacity was observed in multivariate linear regression. CONCLUSIONS: It is well known that biomass combustion is a relevant public health problem. The substantial differences in pulmonary functions associated with biomass use as an energy source observed in this cross-sectional study in non-smokers support that also in rural Turkey measures may be in need to reduce this public health problem.

Recurrent posterior reversible encephalopathy syndrome (PRES).

Posterior reversible encephalopathy syndrome is a proposed cliniconeuroradiological entity characterized by headache, altered mental status, cortical blindness, seizures, and other focal neurological signs, and a diagnostic magnetic resonance imaging picture. A variety of different etiologies have been reported like hypertension, pre-eclampsia/eclampsia, cyclosporin A or tacrolimus neurotoxicity, uraemia and porphyria. With early diagnosis and prompt treatment, the syndrome is usually fully reversible. We report a case of recurrent PRES of unknown aetiology following intensive care unit treatment and only moderately elevated blood pressure. Clinicians as well as radiologists must be familiar with this clinically frightening, underdiagnosed condition to assure timely diagnosis and treatment to prevent persistent deficits.

A comparison of different treatment techniques for posterior crossbite in the mixed dentition.

In this retrospective investigation, the changes occurring during the treatment of patients with posterior crossbite in the mixed dentition with the use of expansion plate and quad-helix appliances were evaluated and compared with those resulting from growth and development occurring in a control group of patients of similar age and type of malocclusion. The expansion plate group consisted of 13 patients, the quad-helix group of 14 patients, and the control group consisted of 10 children with transverse posterior crossbites in the mixed dentition. The research material was formed from orthodontic models and lateral and frontal cephalometric radiographs from 37 children. It was observed in this investigation that transverse expansion is achieved by both the expansion plate and quad-helix appliances. However, the average period of treatment was 1.2 years for the expansion plate, and 0.6 years for the quad-helix appliance. Although posterior crossbite was corrected in a fairly short period of time, the quad helix appliance caused considerable buccal tipping of the maxillary first permanent molars.

Enlarged gamma band response of neuromagnetic auditory evoked fields in a visually impaired subject.

Under acoustic stimulation a phase-locked response in the gamma band (near 40 Hz) in the latency range between 20 and 130 ms is evoked. We report on a considerably visually impaired woman with Grönblad-Strandberg syndrome which involves degeneration at the level of retina, but has no overt central nervous component to the degeneration. The subject exhibited an extraordinarily high power in the phase-locked gamma band response (GBR) which was found to be more than three, and sometimes more than four, standard deviations above the average of a group of 25 subjects with normal vision. Furthermore, the dipoles of her mismatch reaction and M200 were found to be located posteriorly to the dipoles of the M100. Overall, both enlarged GBR and changed cortical representation could be results of cortical plasticity related to visual impairment.

An epidemiological survey using the Treatment Priority Index (TPI).

The purpose of this study was to evaluate the prevalence of malocclusion and to assess the need for orthodontic treatment among 6-10 year old Turkish primary school children. The Treatment Priority Index (TPI) was used to record and measure the malocclusions. The findings were that 40.38 per cent of the observed population showed normal occlusion, 21.85 per cent had minor manifestations of malocclusion and treatment need was slight, 25.17 per cent of the subjects showed definite malocclusion, 7.54 per cent had severe malocclusion and 5.06 per cent had a very severe handicap with a mandatory treatment requirement. Orthodontic treatment need increased between 6 and 10 years of age. No statistically significant difference was found between the mean TPI values of male and female subjects.

Normal faciolingual inclinations of tooth crowns compared with treatment groups of standard and pretorqued brackets.

Faciolingual inclinations of tooth crowns were measured on plaster casts of normal occlusions and posttreatment orthodontic models of treated cases. Normal anatomic occlusion, standard edgewise and Roth bracket groups of 10 subjects were examined for a change in torque values. On study models, crown inclinations of right and left central teeth to second molar in the upper and lower dental arches were measured to the functional occlusal plane and mean tooth inclinations were calculated. In normal occlusion group, upper central and lateral teeth inclined lingually, lower central teeth inclined slightly labially and lower lateral teeth inclined lingually but the standard deviations of mean values for upper and lower anterior teeth were high. Upper posterior teeth, from canine to molar, had a lingual inclination and lower posterior teeth had a progressively increasing lingual inclination from lateral to molar teeth. In treatment groups, upper central and lateral teeth had labial crown inclination and lower molar teeth had more lingual inclination as compared with the normal occlusion group. No significant variation was found between the mean torque values of standard and Roth treatment groups.

The mechanisms of taurine mediated protection against cell damage induced by hypoxia and reoxygenation.

Taurine administered during hypoxia markedly reduced the cell damage due to O2 deficiency and reoxygenation. Different mechanisms are responsible for the improved survival of the renal cell cultures. Taurine markedly reduces the osmoregulatory deterioration during hypoxia and reoxygenation. Calcium homeostasis was markedly improved. Ca2+ efflux during hypoxia as well as Ca2+ overload during reoxygenation was significantly reduced by the amino acid. The effect of taurine was partly comparable to the effect induced by Ca2+ channel blockers. One of the effects mainly responsible for cellular protection seems to be the taurine-induced acceleration of cellular growth processes in spite of hypoxia and reoxygenation. The spectrum of cytoprotective effects of taurine predisposes this substance to be a physiological protective agent responsible for cellular homeostasis or enantiostasis.

Non-invasive measurement of thyroidal iodine content (TIC) by X-ray fluorescence analysis (XFA).

The determination of thyroidal iodine content by X-ray fluorescence analysis is based on the phenomenon that the gamma radiation of Americium-241 excites stable iodine atoms to emit a characteristic fluorescence radiation which is proportional to the amount of iodine present in the gland. To study this, a stationary system has been developed which consists of a 11.1 GBq Am-241 source and a high-purity Germanium detector with spectrum analysator. Lower limit of detectability of this system corresponds to 0.013 mg per ml of thyroid volume measured sonographically; in-vivo precision given as coefficient of variation of duplicate measurements amounts to 12%. The thyroid is exposed with a radiation dose of 60 microSvs per measurement (approximately 5 % of a Tc-99m scan). Studies carried out in 149 volunteers and 173 patients showed a mean iodine concentration of 0.325 +/- 0.134 mg/ml in healthy persons; decreased iodine concentrations were found in euthyroid goitre patients and hyperthyroid patients with focal functional autonomy or Graves' disease. Iodine concentrations correlated negatively with age and goitre volume. The method is well suited for individual follow-up studies exploring different treatment modalities because of its sensitivity, high reproducibility and low radiation exposure.

The effects of Frankel's function regulator (FR-4) therapy on the treatment of Angle Class I skeletal anterior open bite malocclusion.

The present study attempts to evaluate cephalometrically the effects of Fränkel's function regulator (FR-4) appliance on the treatment of Angle Class I skeletal anterior open bite malocclusion. Forty Turkish children (26 girls and 14 boys), with Angle Class I skeletal anterior open bite, were randomly divided into two groups of 20 (13 girls and 7 boys). Patients who had not undergone treatment served as the control group, whereas a second group was treated with lip-seal training and the FR-4 appliance. Chronologic mean decimal age at initial period of the investigation was 8.7 years in the treated group, and 8.9 years in the control group. Treatment and observation periods were 2 years. Investigation was carried out on lateral cephalograms taken before and after the study period. The results indicate that a spontaneous downward and backward growth direction of the mandible observed in the control group could be changed to a upward and forward direction by FR-4 therapy. The skeletal anterior open bite was successfully corrected through upward and forward mandibular rotation.

[The treatment of secondary malocclusion in patients with periodontal disease]. / Periodontal hastalikli bireylerde sekonder malokluzyonlarin tedavisi.

The loss of osseous support resulting from periodontal disease is an etiological factor in the development of secondary malocclusions. Correction of these malocclusions demand a) advanced techniques, b) an understanding of the biological situation present in the patient with periodontal disease and c) adaptation of these techniques and forces to the reduced support. According to the treatment of malocclusion there are improvements in plaque accumulation and the distribution of occlusal forces. These factors, maintain the long term health of the teeth and their periodontium. These kind of treatment requires the maximum interdisciplinary collaboration.