Reduced Protein Expression of the Na+/Ca2++K+-Exchanger (SLC24A4) in Apical Plasma Membranes of Maturation Ameloblasts of Fluorotic Mice.

Exposure of forming enamel to fluoride results into formation of hypomineralized enamel. We tested whether enamel hypomineralization was caused by lower expression of the NCKX4/SLC24A4 Ca2+-transporter by ameloblasts. Three commercial antibodies against NCKX4 were tested on enamel organs of wild-type and Nckx4-null mice, one of which (a mouse monoclonal) was specific. This antibody gave a prominent staining of the apical plasma membranes of maturation ameloblasts, starting at early maturation. The layer of immuno-positive ameloblasts contained narrow gaps without immunostaining or with reduced staining. In fluorotic mouse incisors, the quantity of NCKX4 protein in ameloblasts as assessed by western blotting was not different from that in non-fluorotic ameloblasts. However, immunostaining of the apical plasma membranes of fluorotic ameloblasts was strongly reduced or absent suggesting that trafficking of NCKX4 to the apical membrane was strongly reduced. Exposure to fluoride may reduce NCKX4-mediated transport of Ca2+ by maturation stage ameloblasts which delays ameloblast modulation and reduces enamel mineralization.

NBCe1 (SLC4A4) a potential pH regulator in enamel organ cells during enamel development in the mouse.

During the formation of dental enamel, maturation-stage ameloblasts express ion-transporting transmembrane proteins. The SLC4 family of ion-transporters regulates intra- and extracellular pH in eukaryotic cells by cotransporting HCO3 (-) with Na(+). Mutation in SLC4A4 (coding for the sodium-bicarbonate cotransporter NBCe1) induces developmental defects in human and murine enamel. We have hypothesized that NBCe1 in dental epithelium is engaged in neutralizing protons released during crystal formation in the enamel space. We immunolocalized NBCe1 protein in wild-type dental epithelium and examined the effect of the NBCe1-null mutation on enamel formation in mice. Ameloblasts expressed gene transcripts for NBCe1 isoforms B/D/C/E. In wild-type mice, weak to moderate immunostaining for NBCe1 with antibodies that recognized isoforms A/B/D/E and isoform C was seen in ameloblasts at the secretory stage, with no or low staining in the early maturation stage but moderate to high staining in the late maturation stage. The papillary layer showed the opposite pattern being immunostained prominently at the early maturation stage but with gradually less staining at the mid- and late maturation stages. In NBCe1 (-/-) mice, the ameloblasts were disorganized, the enamel being thin and severely hypomineralized. Enamel organs of CFTR (-/-) and AE2a,b (-/-) mice (CFTR and AE2 are believed to be pH regulators in ameloblasts) contained higher levels of NBCe1 protein than wild-type mice. Thus, the expression of NBCe1 in ameloblasts and the papillary layer cell depends on the developmental stage and possibly responds to pH changes.

Critical Appraisal of Paediatric Embryonal Cancers Treated with Image-guided Intensity-modulated Proton Therapy.

AIM: To carry out a comprehensive critical appraisal of image-guided intensity-modulated proton therapy practice for craniospinal irradiation (CSI). MATERIALS AND METHODS: An image-guided intensity-modulated proton therapy database of 45 consecutive paediatric patients with central nervous system embryonal malignancies treated between January 2019 and April 2022 were critically appraised for demography, diagnosis, treatment planning strategy and treatment delivery accuracy. RESULTS: Most patients (median age: 7.5 years; male:female ratio: 34:11) had medulloblastoma (56%), followed by recurrent ependymoma (19%), pinealoblastoma (5%), germ cell (5%) and others (15%). The dose to the planning target volume-craniospinal (PTV-CS; length 39.06-79.59 cm) varied from 21 to 35 GyRBE, whereas the combined median dose to craniospinal and boost was 54 GyRBE. In all patients, the 95% isodose line covered the cribriform plate completely and optic nerves mostly, with a median V95% of 100% and 82.96%, keeping Dmax to the lens <3.9 GyRBE. In skeletally immature patients (88.38%), the anterior vertebral body was completely covered in 18.18% and underdosed in 70.15% of the cases, resulting in a median Dmean of 10.11 GyRBE to the oesophagus. Lateral spine coverage was maintained on the edges of the vertebral body in 52.2%, whereas it extended beyond in 48.8%. The median V98% for clinical target volumes and V95% for PTVs of the brain, spine and craniospinal were >97%, with excellent conformity (0.89) and homogeneity (0.07) indices for PTV-CS. All neurological organs at risk received a median Dmax ranging from 36 to 44 GyRBE from the combined CSI and boost regimens. Analysis of patient-specific quality assurance results revealed that 545 (97.67%) planar dosage verification had gamma (3% at 3 mm) values >95%. The online patient set-up verification showed translational and rotational deviation within 2 mm and 0.5° in 88-94% and 97% of the cases. Systematic and random error were within 0.90 mm and 1.71 mm in translation and 0.1° and 0.2° in rotation. CONCLUSION: A change in practice pattern was observed. The findings from our comprehensive critical appraisal add to the growing library of CSI practice and may serve as a reference for inter-institutional comparison.

High-dose salvage re-irradiation in recurrent/progressive adult diffuse gliomas: development of a novel prognostic scoring system.

PURPOSE: Over the past two decades, high-dose salvage re-irradiation (re-RT) has been used increasingly in the multimodality management of adults with recurrent/progressive diffuse glioma. Several factors that determine outcomes following re-RT have been incorporated into prognostic models to guide patient selection. We aimed to develop a novel four-tiered prognostic model incorporating relevant molecular markers from our single-institutional cohort of patients treated with high-dose salvage re-RT for recurrent/progressive diffuse glioma. MATERIAL AND METHODS: Various patient, disease, and treatment-related factors impacting upon survival following salvage re-RT were identified through univariate analysis. Each of these prognostic factors was further subdivided and assigned scores of 0 (low-risk), 1 (intermediate-risk), or 2 (high-risk). Scores from individual prognostic factors were added to derive the cumulative score (ranging from 0 to 16), with increasing scores indicating worsening prognosis. RESULTS: A total of 111 adults with recurrent/progressive diffuse glioma treated with salvage high-dose re-RT were included. We could assign patients into four prognostic subgroups (A=15 patients, score 0-3); (B=50 patients, score 4-7); (C=33 patients, score 8-10); and (D=13 patients, score 11-16) with completely non-overlapping survival curves suggesting the good discriminatory ability. Post-re-RT survival was significantly higher in Group A compared to groups B, C, and D, respectively (stratified log-rank p-value <0.0001). CONCLUSION: There exists a lack of universally acceptable 'standard-of-care' salvage therapy for recurrent/progressive diffuse glioma. A novel four-tiered prognostic scoring system incorporating traditional factors as well as relevant molecular markers is proposed for selecting patients appropriately for high-dose salvage re-RT that warrants validation in a non-overlapping cohort.

A novel hybrid 3D dose reconstruction approach for pre-treatment verification of intensity modulated proton therapy plans.

AIM: A novel hybrid three-dimensional (3D) dose reconstruction method, based on planar dose measured at a single shallower depth, was developed for use as patient-specific quality assurance (PSQA) of intensity modulated proton therapy (IMPT) plans. The accuracy, robustness and sensitivity of the presented method were validated for multiple IMPT plans of varying complexities. METHODS AND MATERIALS: An in-house MATLAB program was developed to reconstruct 3D dose distribution from the planar dose (GyRBE) measured at 3 g cm-2 depth in water or solid phantom using a MatriXX PT ion chamber array. The presented method was validated extensively for 11 single-field optimization (SFO) and multi-field optimization (MFO) plans on Proteus Plus. A total of 47 reconstructed planar doses at different depths were compared against the corresponding RayStation treatment planning system (TPS) and MatriXX PT measurement using a gamma passing rate (γ%) evaluated for 3%/3 mm. The robustness of the reconstruction method with respect to depth, energy layers, field dimensions and complexities in the spot intensity map (SIM) were analysed and compared against the standard PSQA. The sensitivity of the reconstruction method was tested for plans with intentional errors. RESULTS: The presented reconstruction method showed excellent agreement (mean γ% > 98%) and robustness with both TPS-calculated and measured dose planes at all depths (2.97-30 g cm-2), energy layers (82.1-225.5 MeV), field dimensions, target volume (17.7-1000 cm3) and SIMs from both SFO and MFO plans. In comparison to the overall mean ± SD γ% from standard PSQA, the reconstruction method showed reductions in mean γ% within 1% for both standard cubes and clinical plans. The reconstruction method was sensitive enough to detect intentional spot positional errors in a selected energy layer of a plan. CONCLUSION: The presented hybrid reconstruction method is sufficiently accurate, robust and sensitive to estimate planar dose at any user-defined depth. It simplifies the measurement setup and eliminates multiple depth measurements.

High-dose salvage re-irradiation for recurrent/progressive adult diffuse glioma: healing or hurting?

PURPOSE: To report survival outcomes and identify prognostic factors of salvage re-irradiation (re-RT) in recurrent/progressive glioma. METHODS: Medical records of patients treated with high-dose re-RT as part of multi-modality salvage therapy for recurrence/progression of adult diffuse glioma from 2010 to 2019 were analyzed retrospectively. RESULTS: A total of 111 patients developing recurrent/progressive high-grade glioma after adequate upfront treatment at initial diagnosis were included. The first course of radiotherapy (RT) had been delivered to a median dose of 59.4 Gy with an inter-quartile range (IQR) of 54-60 Gy. Median time to recurrence/progression was 4.3 years (IQR = 2.3-7.4 years) while the median time to re-RT was 4.8 years (IQR = 3.6-7.9 years). Re-RT was delivered with intensity-modulated radiation therapy (IMRT) using 1.8 Gy/fraction to a median dose of 54 Gy (IQR = 50.4-55.8 Gy) for a cumulative median equivalent dose in 2-Gy fractions (EQD2) of 104.3 Gy (IQR = 102.6-109.4 Gy). At a median follow-up of 14 months after re-RT, the 1-year Kaplan-Meier estimates of post-re-RT progression-free survival (PFS) and overall survival (OS) were 42.8 and 61.8%, respectively. Univariate analysis identified histological grade at recurrence/progression; histological subtype; disease-free interval (DFI) and time interval between both courses of RT; performance status at re-RT; dose at re-RT and cumulative EQD2; isocitrate dehydrogenase (IDH) mutation; and O6-methyl-guanine DNA methyl transferase (MGMT) gene promoter methylation as significant prognostic factors. Preserved performance status, longer DFI, prolonged time interval between both courses of RT, and presence of IDH mutation were associated with significantly improved PFS on multi-variate analysis. However, only performance status retained independent prognostic significance for OS on multi-variate analysis. Post-treatment changes were seen in 33 (30%) patients on follow-up imaging, with higher cumulative dose (EQD2 ≥ 104.3 Gy) being associated with increased risk of post-re-RT pseudo-progression. CONCLUSION: This clinical audit reports encouraging survival outcomes and identifies key prognostic factors associated with high-dose salvage re-RT in recurrent/progressive glioma.

Prospective Longitudinal Assessment of Quality of Life and Activities of Daily Living as Patient-Reported Outcome Measures in Recurrent/Progressive Glioma Treated with High-dose Salvage Re-irradiation.

AIMS: To evaluate quality of life (QOL) and activities of daily living (ADL) longitudinally in patients treated with salvage re-irradiation for recurrent/progressive glioma. Secondary end points included post-re-irradiation survival. MATERIALS AND METHODS: Patients with diffuse glioma, aged 18-70 years with preserved performance status and unequivocal evidence of recurrence/progression with a minimum 2-year time interval from index radiation therapy were eligible. QOL was assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30) and brain cancer module (BN20). ADL was assessed using a modified Barthel's index. Assessments were carried out longitudinally, first before re-irradiation, at completion of re-irradiation and subsequently periodically on follow-up. Summary scores were calculated from raw scores as per the EORTC scoring manual; higher functional scores and lower symptom scores indicating better QOL. Summary mean scores for the modified Barthel's index were also calculated, with lower scores indicating higher disability. Differences between the summary scores at different time points were tested using the Friedman test. RESULTS: In total, 225 assessments were carried out in 60 patients accrued on the study. A significant improvement in scores was noted for physical function (P < 0.001), emotional function (P = 0.002), cognitive function (P = 0.009) and social functioning (P = 0.047) over time. Role function scores (P = 0.182) and global health status scores (P = 0.074) remained stable. Among symptom scores, fatigue showed a statistically significant improvement over time (P = 0.01), whereas other symptom scores remained largely stable. There was a significant increase in the modified Barthel's index score over time (P = 0.001), suggesting greater functional independence. At a median follow-up of 12.9 months, the 1-year Kaplan-Meier estimates with 95% confidence intervals of post-re-irradiation progression-free survival and overall survival were 45.1% (31.5-58.7%) and 62.2% (49.2-75.2%), respectively. CONCLUSIONS: High-dose salvage re-irradiation in carefully selected patients with recurrent/progressive glioma is associated with stable QOL (preserved functional domains and reduced symptom burden) and improvement in ADL (greater functional independence) over time with encouraging survival outcomes.

Characterization and Performance Evaluation of the First-Proton Therapy Facility in India.

PURPOSE: The purpose of this study is to evaluate the performance characteristic of volumetric image-guided dedicated-nozzle pencil beam-scanning proton therapy (PT) system. MATERIALS AND METHODS: PT system was characterized for electromechanical, image quality, and registration accuracy. Proton beam of 70.2-226.2 MeV was characterized for short- and long-term reproducibility in integrated depth dose; spot profile characteristics at different air gap and gantry angle; positioning accuracy of single and pattern of spot; dose linearity, reproducibility and consistency. All measurements were carried out using various X-ray and proton-beam specific detectors following standard protocols. RESULTS: All electro-mechanical, imaging, and safety parameters performed well within the specified tolerance limit. The image registration errors along three translation and three rotational axes were ≤0.5 mm and ≤0.2° for both point-based and intensity-based auto-registration. Distal range (R90) and distal dose fall-off (DDF) of 70.2-226.2 MeV proton beams were within 1 mm of calculated values based on the international commission on radiation units and measurements 49 and 0.0156× R90, respectively. The R90 and DDF were reproducible within a standard deviation of 0.05 g/cm2 during the first 8 months. Dose were linear from 18.5 (0.011 MU/spot) to 8405 (5 MU/spot) MU, reproducible within 0.5% in 5 consecutive days and consistent within 0.8% for full rotation. The cGy/MU for 70.2-226.2MeV was consistent within 0.5%. In-air X(Y) spot-sigma at isocenter varies from 2.96 (3.00) mm to 6.68 (6.52) mm for 70.2-226.2 MeV. Maximum variation of spot-sigma with air-gap of ±20 cm was ±0.36 mm (5.28%) and ±0.82 mm (±12.5%) along X- and Y-direction and 3.56% for full rotation. Relative spot positions were accurate within ±0.6 mm. The planned and delivered spot pattern of known complex geometry agreed with (γ%≤1) for 1% @ 1 mm >98% for representative five-proton energies at four gantry angle. CONCLUSION: The PT-system performed well within the expected accuracy level and consistent over a period of 8 months. The methodology and data presented here may help upcoming modern PT center during their crucial phase of commissioning.

Planning and delivery of whole brain radiation therapy with simultaneous integrated boost to brain metastases and synchronous limited-field thoracic radiotherapy using helical tomotherapy: a preliminary experience.

Lung cancer is the commonest source of brain metastases, which has been traditionally treated with Whole Brain Radiation Therapy (WBRT) with or without focal boost. We herein report our preliminary experience of the planning and delivery of WBRT with Simultaneous Integrated Boost (SIB) to brain metastases along with synchronous limited-field thoracic radiotherapy using Helical TomoTherapy in four patients with lung cancer. All plans were iteratively optimized for maximal target volume coverage and organ-at-risk (OAR) sparing. Standardized dose metrics were used for plan evaluation. All treated regions were imaged with a megavoltage computed tomography (CT) prior to treatment and co-registered with planning CT for image-guidance. Helical TomoTherapy was able to achieve highly conformal and homogeneous dose distributions with excellent OAR sparing both in the brain and the chest. The mean (standard deviation) Dose Homogeneity Index (DHI) and Conformity Index (CI) was 0.06 (0.01) & 0.79 (0.07); 0.04 (0.02) & 0.57 (0.22); and 0.03 (0.02) & 0.77 (0.06) for whole brain, brain metastases, and chest, respectively. The mean monitor units (MU) per fraction and time taken for delivery were 8595 and 9898 MU and 9.8 and 11.3 minutes for the brain and chest plans, respectively. Although the dosimetric equivalence of SIB to a single fraction radiosurgery might still be questionable, our preliminary experience of WBRT with SIB to individual brain metastases using Helical TomoTherapy has been encouraging. In addition, it allows synchronous irradiation of other involved primary or metastatic sites for palliative effect.

Does intensity-modulated stereotactic radiotherapy achieve superior target conformity than conventional stereotactic radiotherapy in different intracranial tumours?

AIMS: To compare the dosimetric outcome of various conventional stereotactic radiotherapy (SRT) techniques with intensity-modulated stereotactic radiotherapy (IMSRT) in brain tumours of varying shape, size, location and proximity to organs at risk (OARs). MATERIALS AND METHODS: Fused computed tomography and magnetic resonance imaging datasets of four patients with different brain tumours previously treated with non-coplanar static conformal fields (SCF) were re-planned on the BrainScan treatment planning system using non-coplanar conformal arcs (CA), dynamic conformal arcs (DCA) and IMSRT with coplanar (IMSRT_CP) or non-coplanar (IMSRT_NCP) beam arrangement. Beam shaping and intensity modulation were carried out using a BrainLab micromultileaf collimator. The primary objective for each plan was to encompass >or=99% of the planning target volume (PTV) by >95% of the prescribed dose while minimising the dose to OARs. RESULTS: The mean PTV coverage in SCF, CA, DCA, IMSRT_NCP and IMSRT_CP was 99.2, 99.5, 99.4, 99.2 and 99.2%, respectively. The highest dose within the target was <107% of the prescribed dose in all plans. Conformity was found to vary depending on the shape and location of the target. The best mean conformity index, ranging from 0.74 (CA) to 0.84 (IMSRT_NCP) was observed in spherical tumours. Among the three conventional SRT techniques, DCA and SCF appeared comparable (mean conformity index 0.72 and 0.71, respectively) and more conformal than CA (mean conformity index 0.67). In all cases, IMSRT showed better target conformity than conventional SRT techniques with a mean conformity index of 0.83 for non-coplanar and 0.81 for coplanar beam arrangement. The maximum improvement in conformity index was observed for IMSRT_NCP in complex, concave and irregularly shaped targets. The volume of normal brain and other OARs irradiated to high (>or=80%) and low (>or=30%) dose varied depending on the tumour shape, size, and location, but was essentially comparable in all three conventional SRT techniques. IMSRT (both coplanar as well as non-coplanar) reduced the volume of normal brain being irradiated to moderate to high doses compared with conventional SRT techniques, more so for large and irregular targets. CONCLUSIONS: DCA and SCF are preferred conventional SRT techniques in terms of target conformity and reduction of doses to OARs. The use of IMSRT_NCP further improves conformity and reduces doses to OARs in a range of brain tumours commonly considered for stereotactic irradiation.

Factors influencing cosmetic outcome in breast conservation.

With more than 1 million new cases each year, female breast cancer is the second most common cancer in the world and the most common cancer among women. Breast cancer involves a multimodality treatment and a co-ordinated approach from various specialties. Breast-conserving therapy (BCT) is increasingly being integrated into the management of breast cancer. The obvious advantages of BCT are equivalent local and distant control rates as compared with mastectomy and the preservation of the breast. However, the key to a successful BCT is achieving a cosmetic outcome that is acceptable to the patient and the physician. Cosmesis in breast cancer is the end result of a range of factors that fall under the broad heads of surgery, radiotherapy, chemotherapy and hormonal treatment. All of these modalities can play a role in compromising breast cosmesis. This overview discusses the factors that are critical in affecting the final cosmetic outcome in patients with BCT.

Therapy for glioma: Indian perspective.

Central nervous system (CNS) are rare neoplasms with considerable heterogeneity and variation. The most common primary lesions of CNS are gliomas. A majority of the data about the demography and management of gliomas has emerged from the west. However, there may be considerable variation in the presentation, behavior, and response to treatment between patients in the western world and the Asian population. This article discusses gliomas with special reference to data from oncology centers in India.

Comparison of Epidemiology and Outcomes in Neuro-Oncology Between the East and the West: Challenges and Opportunities.

Although neoplasms of the brain and central nervous system (CNS) are relatively uncommon, comprising only 1-2% of the overall cancer burden, they represent a substantial source of morbidity and mortality worldwide. The age-adjusted annual incidence of CNS tumours is reportedly low; however, there is substantial global variability in its incidence, with nearly a five-fold difference between regions with the highest rates in developed countries in the West and those with the lowest rates in developing countries in South-East Asia, including India, possibly attributable to key differences in environmental factors, genetic susceptibilities and cultural practices, as well as resource constraints in low-middle income countries precluding precise ascertainment and accurate diagnosis. The burden of CNS tumours is further compounded by the fact that they require highly specialised and skilled multidisciplinary care, including access to modern neuroimaging, neurosurgery, neuropathology and molecular biology, radiotherapy, chemotherapy and rehabilitation services, which may not be widely available in an integrated manner in large parts of the world with a large variation in clinical pathways, non-uniformity of care and resultant heterogeneity in clinical outcomes. CNS tumours encompass a heterogeneous spectrum of histopathological entities with differences in presentation, distinct molecular/genetic alterations, diverse biological behaviour and varying clinical outcomes. Survival is highly dependent on histology, grade and molecular biology, but varies widely across continents, even for the same tumour type and grade. In general, survival is higher in children with primary brain tumours than in adults, largely due to the differences in histological distribution across age groups. However, there is widespread variability, with 5-year survival for paediatric brain tumours being <40% in some low-middle income countries compared with 70-80% in the developed world. This review compares the descriptive epidemiology and clinical outcomes of primary brain tumours between the East and the West that pose unique challenges but also provide new opportunities in contemporary neuro-oncological practice.

Dosimetric comparison of conventional radiograph- and three-dimensional computed tomography-based planning using dose volume indices for partial breast intraoperative implants.

AIMS: The dosimetric outcomes of radiograph- and computed tomography-based plans generated with various optimisation strategies were compared using dose volume indices for partial breast intraoperative implants. MATERIALS AND METHODS: Eighteen patients with early stage breast cancer underwent conventional orthogonal radiograph and computed tomography to generate dosimetric data. Catheter reconstruction and delineation of the lumpectomy cavity, the planning target volume (PTV) and the ipsilateral breast were carried out on computed tomography images. For each patient, geometrically optimised plans (P(xray) and P(CT)) were generated using the active loading length based on the PTV defined from radiographs (PTV(xray)) and computed tomography (PTV(CT)). The plan P(CT) was further optimised graphically and yielded P(graphical). Plans were compared using the coverage index (CI), the external volume index (EI), the dose homogeneity index (DHI), the overdose volume index (OI) and the conformal index (COIN). RESULTS: The mean CI of the lumpectomy cavity estimated from P(xray), P(CT) and P(graphical) was 0.80, 0.82 and 0.92, respectively. The corresponding values for PTV(CT) were 0.69, 0.71 and 0.85. P(graphical) showed an increase in CI by 23 and 19% with respect to P(xray) and P(CT) (P<0.001 in all) with a decrease in DHI from 0.81 to 0.71 (P<0.001) and increase in OI from 0.041 to 0.087 (P<0.001). The EI was highest in P(xray) (mean 44 cm(3)) as compared with 25 cm(3) in P(CT) and 30 cm(3) in P(graphical). A significant improvement in COIN was observed in P(graphical) (mean 0.68) compared with P(xray) (0.48) and P(CT) (0.58) (P<0.001). CONCLUSIONS: Objective dosimetric evaluation on three-dimensional computed tomography confirms its superiority over conventional two-dimensional radiograph-based planning in terms of a reduction in normal breast irradiated with the prescription dose and improvement in conformity. Interactive graphical optimisation based on the target volume in computed tomography further improves conformity with a reduction in dose homogeneity. The use of dose volume indices allows the comparison of different plans and can be used as a tool to correlate dosimetric with clinical outcome.

Suprasellar haemangiopericytoma--challenges in diagnosis and treatment.

Haemangiopericytomas of central nervous system (CNS) were first defined as a separate entity in 1942. Previously they were either considered to be a histological variant of an angioblastic meningioma or a distinctive mesenchymal neoplasm. Most commonly they are located in parasagittal and falcine region. Tumours in the sellar/parasellar location are very rare and commonly escape diagnosis before operation. They are characterised by high vascularity, a high rate of local recurrence and extraneuronal metastasis. We report a 35-year-old man with a suprasellar hemangiopericytoma who presented with bilateral diminution of vision in both eyes and frontal headache. Six months after the first operation, he developed a large local recurrence. He again underwent tumour decompression followed by postoperative conformal radiotherapy and is currently asymptomatic and stable clinically and radiologically. The various differential diagnoses, the importance of a preoperative suspicion of this diagnosis and management are issues discussed in this illustrated review.

An atypical presentation of recurrent temporal lobe meningioma with external auditory canal mass.

Extracranial spread of recurrent meningiomas involving the middle ear is rare. We present the case of a 59-year-old woman with headache and swelling of scalp over the right temporal region. MRI revealed a lesion in the right temporal lobe suggestive of meningioma. She underwent complete surgical excision of the lesion followed by post-operative radiotherapy. After 1 year, she presented with right-sided otalgia and a middle-ear mass extruding into the external auditory canal. She was re-operated and histopathology was anaplastic meningioma. We are discussing this unusual pattern of recurrence in our patient with a review of literature.

Rechallenge temozolomide in glioma: A case series from India.

INTRODUCTION: Temozolomide (TMZ) is an integral part of upfront treatment of high-grade gliomas. It is administered postsurgery as concurrent therapy with radiation and subsequently as adjuvant chemotherapy for 6-12 cycles. It is unknown whether rechallenge of salvage TMZ in previously treated high-grade glioma has any efficacy. MATERIAL AND METHODS: Patients treated with salvage rechallenged TMZ between January 2015 and August 2016 were included for this retrospective analysis. SPSS version 20 was used for this analysis. Time to event analysis was performed using the Kaplan-Meier method. Progression-free survival (PFS) and overall survival (OS) were estimated. The maximum grade of toxicity was noted in accordance with CTCAE version 4.02. RESULTS: A total of 23 patients were selected for analysis with the median age being 43 years (range: 26-69 years). The tumor histopathology at baseline was astrocytoma Grade 2 in 1 patient, oligodendroglioma Grade 2 in 3 patients, anaplastic astrocytoma in 7 patients, anaplastic oligodendroglioma in 2 patients, and glioblastoma in 10 patients. All of them had previously received TMZ. The median numbers of previous TMZ cycles received were 6 (4-18). The median time to failure postlast treatment was 24 months (5-72 months). The median number of cycles of rechallenged salvage TMZ administered was 6 cycles (range: 1-18). Grade 3-4 myelosuppression was seen in 3 patients (13.4%). The median PFS was 459 days (95% confidence interval: 212.1-705.9). The median OS was 25 months. Six-month OS and 1-year OS were 81.4% and 75.1%, respectively. CONCLUSION: Rechallenge with TMZ in recurrent glioma that had previously responded to TMZ is associated with improvement in PFS and OS and has a sufficiently long disease-free interval.

A case series of salvage CCNU in high-grade glioma who have previously received temozolomide from a tertiary care institute in Mumbai.

INTRODUCTION: In our center, we routinely use CCNU (Lomustine) as salvage treatment in high-grade glioma patients who cannot afford bevacizumab. This exploratory analysis was done to report the efficacy and toxicity associated with this regimen. METHODS: Patients who were treated with salvage CCNU (postexposure to temozolomide) between January 2015 and August 2016 were included for this retrospective analysis. SPSS version 16 was used for this analysis. Time-to-event analysis was performed using the Kaplan-Meier method. Progression-free survival (PFS) and overall survival (OS) were estimated. The maximum grade of toxicity during salvage CCNU was noted in accordance with CTCAE version 4.02. RESULTS: In the stipulated period, 16 patients were selected for the analysis. The median age of patients was 43 years (range 15-63 years), and 12 (80.0%) patients were males. The Eastern Cooperative Oncology Group performance status was 0-1 in 11 patients (73.3%) and 2-4 in 4 patients (26.7%). The tumor histopathology at diagnosis was glioblastoma in ten patients (66.6%), anaplastic astrocytoma in four (26.7%) patients, and anaplastic oligodendroglioma in one patient (6.7%). Grade 3-4 myelosuppression was seen in five patients (33.3%). The median PFS and OS were 192 days (95% confidence interval [CI]: 156.0-227.5 days) and 282 days (95% CI: 190.9-373.1 days), respectively. CONCLUSION: CCNU is associated with modest treatment outcomes in recurrent/relapsed high-grade gliomas. The high rate of myelosuppression is a concern. Urgent efforts are required to improve upon these results.

Ameloblast Modulation and Transport of Cl⁻, Na⁺, and K⁺ during Amelogenesis.

Ameloblasts express transmembrane proteins for transport of mineral ions and regulation of pH in the enamel space. Two major transporters recently identified in ameloblasts are the Na(+)K(+)-dependent calcium transporter NCKX4 and the Na(+)-dependent HPO4 (2-) (Pi) cotransporter NaPi-2b. To regulate pH, ameloblasts express anion exchanger 2 (Ae2a,b), chloride channel Cftr, and amelogenins that can bind protons. Exposure to fluoride or null mutation of Cftr, Ae2a,b, or Amelx each results in formation of hypomineralized enamel. We hypothesized that enamel hypomineralization associated with disturbed pH regulation results from reduced ion transport by NCKX4 and NaPi-2b. This was tested by correlation analyses among the levels of Ca, Pi, Cl, Na, and K in forming enamel of mice with null mutation of Cftr, Ae2a,b, and Amelx, according to quantitative x-ray electron probe microanalysis. Immunohistochemistry, polymerase chain reaction analysis, and Western blotting confirmed the presence of apical NaPi-2b and Nckx4 in maturation-stage ameloblasts. In wild-type mice, K levels in enamel were negatively correlated with Ca and Cl but less negatively or even positively in fluorotic enamel. Na did not correlate with P or Ca in enamel of wild-type mice but showed strong positive correlation in fluorotic and nonfluorotic Ae2a,b- and Cftr-null enamel. In hypomineralizing enamel of all models tested, 1) Cl(-) was strongly reduced; 2) K(+) and Na(+) accumulated (Na(+) not in Amelx-null enamel); and 3) modulation was delayed or blocked. These results suggest that a Na(+)K(+)-dependent calcium transporter (likely NCKX4) and a Na(+)-dependent Pi transporter (potentially NaPi-2b) located in ruffle-ended ameloblasts operate in a coordinated way with the pH-regulating machinery to transport Ca(2+), Pi, and bicarbonate into maturation-stage enamel. Acidification and/or associated physicochemical/electrochemical changes in ion levels in enamel fluid near the apical ameloblast membrane may reduce the transport activity of mineral transporters, which results in hypomineralization.

Slc26a3/Dra and Slc26a6 in Murine Ameloblasts.

Formation of apatite crystals during enamel development generates protons. To sustain mineral accretion, maturation ameloblasts need to buffer these protons. The presence of cytosolic carbonic anhydrases, the basolateral Na(+) bicarbonate cotransporter Nbce1, and the basolateral anion exchanger Ae2a,b in maturation ameloblasts suggests that these cells secrete bicarbonates into the forming enamel, but it is unknown by which mechanism. Solute carrier (Slc) family 26A encodes different anion exchangers that exchange Cl(-)/HCO3 (-), including Slc26a3/Dra, Slc26a6/Pat-1, and Slc26a4/pendrin. Previously, we showed that pendrin is expressed in ameloblasts but is not critical for enamel formation. In this study, we tested the hypothesis that maturation ameloblasts express Dra and Slc26a6 to secrete bicarbonate into the enamel space in exchange for Cl(-). Real-time polymerase chain reaction detected mRNA transcripts for Dra and Slc26a6 in mouse incisor enamel organs, and Western blotting confirmed their translation into protein. Both isoforms were immunolocalized in ameloblasts, principally at maturation stage. Mice with null mutation of either Dra or Slc26a6 had a normal dental or skeletal phenotype without changes in mineral density, as measured by micro-computed tomography. In enamel organs of Slc26a6-null mice, Dra and pendrin protein levels were both elevated by 52% and 55%, respectively. The amount of Slc26a6 protein was unchanged in enamel organs of Ae2a,b- and Cftr-null mice but reduced in Dra-null mice by 36%. Our data show that ameloblasts express Dra, pendrin, or Slc26a6 but each of these separately is not critical for formation of dental enamel. The data suggest that in ameloblasts, Slc26a isoforms can functionally compensate for one another.