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.

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 (AU)

Association of UGT1A6 gene polymorphism with clinical outcome in pediatric epileptic patients on sodium valproate monotherapy.

Pediatric epilepsy comprises chronic neurological disorders characterized by recurrent seizures. Sodium valproate is one of the common antiseizure medications used for treatment. Glucuronide conjugation is the major metabolic pathway of sodium valproate, carried out by the enzyme uridine 5'-diphosphate (UDP) glucuronosyl transferase (UGT) whose gene polymorphisms may alter the clinical outcome. The objective of this study was to assess the association between UGT1A6 genetic polymorphism and clinical outcome in terms of efficacy and tolerability in pediatric epileptic patients on sodium valproate monotherapy. Pediatric epileptic patients (n=65) aged 2-18 years receiving sodium valproate monotherapy for the past one month were included. Genetic polymorphism patterns of UGT1A6 (T19G, A541G, A552C) were evaluated by PCR-RFLP. Clinical outcome was seizure control during the 6 months observation period. Tolerability was measured by estimating the hepatic, renal, and other lab parameters. Out of 65 patients, TT (40%), TG (57%), and GG (3%) patterns were observed in UGT1A6 (T19G) gene, AA (51%), AG (40%), and GG (9%) in (A541G) gene, and AA (43%), AC (43%), and CC (14%) in (A552C) gene. No statistical difference in clinical outcome was found for different UGT1A6 genetic polymorphism patterns. We concluded that different patterns of UGT1A6 genetic polymorphism were not associated with the clinical outcome of sodium valproate in terms of efficacy and tolerability. Sodium valproate was well-tolerated among pediatric patients with epilepsy and can be used as an effective antiseizure medication.

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.

Genome-level insights into the operation of an on-site biological wastewater treatment unit reveal the importance of storage time.

On-site wastewater treatment systems are gaining popularity in areas where centralized wastewater treatment is not available. In the current case study a domestic activated sludge system was investigated, where treated effluent was stored in a short-term (1 week turn-over time) and a long-term (over 2-3 months) storage tank and was then used for irrigation. This design provided a unique opportunity to assess the chemical and microbial changes of the effluent upon storage. Long-term storage greatly improved both the chemical quality and the degradation efficiency of most organic micropollutants examined, including petroleum hydrocarbons and the pesticide diethyltoluamide. Taxonomic profile of the core microbiome of the effluent was also influenced upon storage. Relative abundance values of the members of Azoarcus and Thauera genera, which are important in degrading polycyclic aromatic hydrocarbons compounds, clearly indicated the biodegrading activity of these microbes across samples. The abundance of xenobiotics degradation functions correlated with the observed organic micropollutant degradation values indicating efficient microbial decomposition of these contaminants. Functions related to infectious diseases also had the highest abundance in the short-term storage tank corresponding well with the relative abundance of indicator organisms and implying to the significance of storage time in the elimination of pathogens. Based on these results, small, on-site wastewater treatment systems could benefit from long-term storage of wastewater effluent.

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.

Association of UGT1A6 gene polymorphism with clinical outcome in pediatric epileptic patients on sodium valproate monotherapy

Pediatric epilepsy comprises chronic neurological disorders characterized by recurrent seizures. Sodium valproate is one of the common antiseizure medications used for treatment. Glucuronide conjugation is the major metabolic pathway of sodium valproate, carried out by the enzyme uridine 5′-diphosphate (UDP) glucuronosyl transferase (UGT) whose gene polymorphisms may alter the clinical outcome. The objective of this study was to assess the association between UGT1A6 genetic polymorphism and clinical outcome in terms of efficacy and tolerability in pediatric epileptic patients on sodium valproate monotherapy. Pediatric epileptic patients (n=65) aged 2-18 years receiving sodium valproate monotherapy for the past one month were included. Genetic polymorphism patterns of UGT1A6 (T19G, A541G, A552C) were evaluated by PCR-RFLP. Clinical outcome was seizure control during the 6 months observation period. Tolerability was measured by estimating the hepatic, renal, and other lab parameters. Out of 65 patients, TT (40%), TG (57%), and GG (3%) patterns were observed in UGT1A6 (T19G) gene, AA (51%), AG (40%), and GG (9%) in (A541G) gene, and AA (43%), AC (43%), and CC (14%) in (A552C) gene. No statistical difference in clinical outcome was found for different UGT1A6 genetic polymorphism patterns. We concluded that different patterns of UGT1A6 genetic polymorphism were not associated with the clinical outcome of sodium valproate in terms of efficacy and tolerability. Sodium valproate was well-tolerated among pediatric patients with epilepsy and can be used as an effective antiseizure medication.

A cadaveric study of variations of external iliac artery and its implication in trauma and radiology.

OBJECTIVES: A severe and potentially lethal complication in pelvic injuries is arterial bleeding commonly involving the iliac arteries. Hence, the objective of our study was to systematically document the morphology and variations of the external iliac artery in human cadaveric pelvises. MATERIALS AND METHODS: Study was conducted on 48 pelvic halves which were obtained by making mid-line saw cuts through formalin embalmed adult human male cadaveric pelvises. The external iliac artery was cleaned, its length and diameter were measured using a scale. Following parameters were noted: variations of the external iliac artery in terms of its location, course, termination, relations with other vessels and variations in its branching pattern. RESULTS: Variations related to the morphology and branching pattern of the external iliac artery was observed in 20 hemipelvises (42%). Nine (19%) hemipelvises showed morphological variations of the artery (looped, tortuous, curved, twisted or 'S' shaped). Variations in the branching pattern of the artery were seen in 6 (13%) hemipelvises and the artery was superficial or medial to the external iliac vein in 5 (10%) hemipelvises. Mean length of the artery was 10cm on the right and 9.9cm on the left side of the pelvis. Its mean diameter was 0.94mm on the right and 0.99mm on left side. CONCLUSION: Diagnostic and interventional radiologic procedures on the pelvic arteries are becoming more frequent, and hence in here, we have performed the morphological study of the external iliac artery is necessary to guide interventional procedures.

An assessment and comparison of nasolabial aesthetics in bilateral clefts using the anatomical subunit-based scale: a nasoalveolar moulding versus non-nasoalveolar moulding study.

Nasoalveolar moulding is a presurgical orthopaedic technique used to improve the outcomes of bilateral clefts. However, the lack of a validated scale tailored to bilateral clefts makes it difficult to quantify the merits of nasoalveolar moulding and compare it to other techniques. In this study, a recently published anatomical subunit scale was used to evaluate and compare the early effects of nasoalveolar moulding. Two groups of similarly treated bilateral cleft patients were included: one in which patients underwent presurgical nasoalveolar moulding and one in which they did not. The nasolabial aesthetics were evaluated on two-dimensional photographs at 6 months post cheiloplasty. Cupid's bow, vermilion symmetry, vermilion notching, premaxillary show at rest, scar aesthetics, columella height, columella height, and bialar width were all significantly better in the nasoalveolar moulding group. Using the new scale, it was found that nasolabial aesthetics at 6 months post cheiloplasty were significantly better in patients who had undergone nasoalveolar moulding in infancy.

Prenatal diagnosis and implications of microphthalmia and anophthalmia with a review of current ultrasound guidelines: two case reports.

BACKGROUND: Microphthalmia and anophthalmia are rare congenital fetal abnormalities. The combined incidence is estimated at 1 in 10,000 births. These two conditions arise from complex and incompletely understood genetic and/or environmental causes. Prenatal diagnosis is neither frequent nor easy and relies on precise, high-quality ultrasonography. Current antenatal ultrasound protocols for imaging of the fetal eye are inconsistent and inadequate to screen for the spectrum of ocular malformations, and there are no clear guidelines on detection of these rare abnormalities. Our study of two cases highlights the importance of early detection, and we review current practice and suggest a definitive fetal imaging protocol. CASE PRESENTATION: We present two antenatal cases, one each of microphthalmia and anophthalmia, both diagnosed at the morphology scan at our tertiary fetal medicine unit. In both cases, the parents (a 36-year-old woman of Mauritanian ethnicity and a non-consanguineous partner of Nepalese descent, and a 31-year-old Caucasian woman and non-consanguineous Caucasian partner) elected to terminate their pregnancies and made unremarkable recoveries. Subsequent fetal autopsy confirmed the ultrasound scan findings. CONCLUSIONS: We recommend that antenatal ultrasound guidelines are updated to specify use of a curvilinear transducer (2-9 MHz) to image both orbits in the axial and coronal planes, aided by use of a transvaginal probe when the transabdominal approach is inadequate to generate these images. When applicable, three-dimensional reverse-face imaging should be obtained to aid the diagnosis. The presence, absence, or non-visualization of lenses and hyaloid arteries should be documented in reports and these cases referred for a tertiary-level ultrasound scan and fetal medicine review. Imaging of the orbits should occur from 12 weeks' gestation. Magnetic resonance imaging and amniocentesis with chromosome microarray testing may provide additional genetic and structural information that may affect the overall morbidity associated with a diagnosis of microphthalmia or anophthalmia.

Hyperthermia effect and antibacterial efficacy of Fe3+ /Co2+ co-substitutions in ß-Ca3 (PO4 )2 for bone cancer and defect therapy.

The combined effect of cobalt and iron substitutions in ß-Ca3 (PO4 )2 as a potent material for application in hyperthermia and as a bone substitute is presented. Structural analysis reveals the preferential accommodation of Co2+ and Fe3+ at the Ca2+ (5) sites of ß-Ca3 (PO4 )2 until the limit of ∼10 mol % and, thereafter, prefer Ca2+ (4) lattice sites. Occupancy of both the Co2+ and Fe3+ ions induces a significant contraction of the ß-Ca3 (PO4 )2 unit cell. The Co2+ /Fe3+ co-substitutions in ß-Ca3 (PO4 )2 display magnetic characteristics that enhances hyperthermia effect. In addition, the presence of Co2+ in ß-Ca3 (PO4 )2 enunciates pronounced antibacterial efficacy against tested microorganisms. Nevertheless, the enhanced level of Co2+ in ß-Ca3 (PO4 )2 results to induce significant toxicity. The biocompatibility of the synthesized thermoseeds is verified from the hemolytic tests and cytotoxicity test performed on human sarcoma cell line MG-63. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1317-1328, 2018.

Descendens vagohypoglossi: rare variant of the superior root of ansa cervicalis.

Knowledge of variants in the formation and position of the ansa cervicalis is important in head and neck surgery, specifically in reconstructions of the tongue that use the infrahyoid muscles, and in the anastomosis of the ansa cervicalis to the recurrent laryngeal nerve when the laryngeal muscles have been paralysed. We describe a rare variant of the superior root of the ansa cervicalis, which had a contribution from the vagus and hypoglossal nerves. The inferior root was formed by the C2 and C3 ventral rami, but it passed medial to the internal jugular vein before it joined the superior root to form the loop.

An anatomical subunit-based outcome assessment scale for bilateral cleft lip and palate.

As there is currently no internationally accepted outcome measurement tool available for complete bilateral cleft lip and palate (CBCLP), the goal of this prospective study was to develop a numerical evaluation scale that allows reliable scoring of this cleft deformity. Our cohort comprised 121 Indian subjects with CBCLP who underwent surgical repair (mean age at time of surgery 6.53 months) using a modified Millard technique. A panel of three professionals evaluated each subject's outcome of bilateral cleft lip repair 6 months postoperatively on two-dimensional (2D) full-face photographs in the frontal view and worm's eye view. A simple two-point rating system was applied to separately analyse a total of 12 components of lip, nose, and scar. The results and mean scores for the analysed anatomical areas were 2.2±1.01 (max=3) for nose, 5.4±1.54 (max=8) for lip, and 1.9±1.3 (max=3) for scar, with a total score 7.7±2.21 (max=12) indicating a good surgical outcome. The inter-examiner ICC for nose, lip, scar, and total score was calculated at 0.836, 0.889, 0.723, and 0.927 respectively and indicated a strong level of repeatability and reliability that was highly significant (P<0.001). In conclusion, we were able to develop and test a scoring system for measuring outcomes in CBCLP that warrants simplicity of use, reliability and reproducibility.

Trend of human brucellosis over a decade at tertiary care centre in North Karnataka.

BACKGROUND: Brucellosis is an important zoonotic disease. India having a major agrarian population is expected to have a higher prevalence. However, due to lack of laboratory facility or awareness among clinicians, the disease is largely underreported. The aim of this study was to know the prevalence and trend of human brucellosis over a decade, in patients attending a teaching hospital in North Karnataka, and to understand their geographical distribution. MATERIALS AND METHODS: The study was conducted from January 2006 to December 2015 at a tertiary care teaching hospital in North Karnataka. A total of 3610 serum samples were evaluated from suspected cases of brucellosis. All serum samples were initially screened by Rose Bengal plate test, and positive samples were further analysed by Serum agglutination test (SAT) using standard Brucella abortus antigen from Indian Veterinary Research Institute, Izatnagar, Uttar Pradesh, India. A titre above or equal to 1:80 IU/ml was considered as positive. Demographic data such as age, sex and native place of these patients were also analysed. RESULTS: We observed that human brucellosis is present in North Karnataka. The overall seropositivity of brucellosis in suspected cases was 5.1%. The positive titres ranged from 1:80 to 163,840 IU/ml. The majority of the patients were from Gadag, Koppal and Haveri districts of North Karnataka. CONCLUSION: Our study confirms the presence of human brucellosis in the northern part of Karnataka. Further studies to understand the prevalence of animal brucellosis in these areas will help in implementing prevention measures.

A new approach to exfoliative cytology: A comparative cytomorphometric study.

CONTEXT: Early detection of oral premalignancy and malignancy using simple screening aids play a promising role in curbing the disease. AIM: The primary aim of this study is to evaluate and the secondary aim of this study is to compare the cytomorphometry and cellular atypia in keratinocytes obtained from oral rinse and conventional exfoliative cytology in normal oral mucosa and clinically diagnosed oral leukoplakia. MATERIALS AND METHODS: The study comprised of 55 clinically diagnosed cases of leukoplakia and 55 age and sex matched normal controls. Smears were prepared using oral rinse technique followed by the conventional exfoliative cytology. Papanicoloau stained smears were evaluated for atypia and subjected to image analysis. Based on the presence of atypia they were further divided into three groups (Group 1-cases with atypia, Group 2-without atypia and Group 3-normal controls) and analyzed. Statistical analysis used one-way analysis of variance followed by Tukey Honestly Significant Difference test for intergroup analysis and unpaired students t-test to compare the two methods. RESULTS: Smears prepared with both methods demonstrated atypia in 18 cases. The cellular diameter and cellular area (CA) were progressively increased from Group 1 through Groups 2 and 3 in both the smears. Nuclear diameter and nuclear area and nuclear cytoplasmic ratio progressively decreased from Group 1 through Groups 2 and 3. Both the methods showed no significant differences among the cellular parameters except in normal controls. CONCLUSION: Cytomorphometric analysis of keratinocytes obtained with oral rinse method and wooden spatula can serve as a useful screening aid to detect oral leukoplakia. Oral rinse method being more convenient results in smears of better quality.

Correlation of vermilion symmetry to alveolar cleft defect in unilateral cleft lip repair.

Asymmetry is a major problem in repaired unilateral cleft lip (UCL). One of the important manifestations of this is the asymmetry of the vermilion. The aim of this study was to correlate the severity of the asymmetry in the vermilion to the size of the alveolar defect. Twenty patients aged between 6 and 18 months with complete unilateral cleft lip, alveolus, and palate were included. An impression of each patient's alveolus at the time of cheiloplasty was taken using silicon rubber base material, and a study cast was prepared. The width of the cleft alveolus was measured on these casts using a transparent grid. Frontal photographs were taken at 6 months postoperative and vermilion symmetry was measured as the ratio between the cleft and non-cleft sides. The results obtained in this study showed a direct correlation between the size of the alveolar defect and the vermilion symmetry in repaired UCL. The wider the cleft alveolus and greater the antero-posterior discrepancy, the greater is the vermilion asymmetry. The asymmetry of the vermilion in UCL after repair is directly dependent on the size of the alveolar defect. The alveolar discrepancy causes 'in-rolling' of the vermilion on the cleft side and affects the vermilion symmetry.