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. 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.

Neurotrophins: Role in Placental Growth and Development.

Neurotrophins, a family of closely related proteins, were originally identified as growth factors for survival, development, and function of neurons in both the central and peripheral nervous systems. Subsequently, neurotrophins have been shown to have functions in immune and reproductive systems. Neurotrophins like nerve growth factor and brain-derived neurotrophic factor (BDNF) are known to play an important role during pregnancy in the process of placental angiogenesis and maturation. Several studies have demonstrated the presence of neurotrophins in the human placenta. The current chapter reviews studies demonstrating the role of neurotrophins during pregnancy particularly in placental development. This chapter also focuses on the regional changes in neurotrophins in the human placenta and its interactions with other growth factors. Future research is needed to understand the mechanisms through which neurotrophins influence the growth and development of the placenta and pregnancy outcome.

Neurotrophin levels in different regions of the placenta and their association with birth outcome and blood pressure.

INTRODUCTION: Our recent study in preeclampsia indicates differential oxidative stress in various regions of the placenta. Oxidative stress is known to influence neurotrophin levels. We therefore hypothesize that placental regional differences in oxidative stress will also lead to differences in neurotrophin levels. METHODS: The current study examines the levels of neurotrophins, brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in different regions of the placenta in 50 normotensive control women and 47 women with preeclampsia (21 delivering at term and 26 delivering preterm). Placentae were collected from four different regions: central maternal (CM), central fetal (CF), peripheral maternal (PM) and peripheral fetal (PF). RESULTS: BDNF levels were higher in CF region as compared to CM (p < 0.01), PM (p < 0.01) and PF (p < 0.05) regions of the placenta in the control group. There was no regional change in NGF levels in any of the groups. Analysis between groups indicated higher NGF levels in CM (p < 0.01), PM (p < 0.05) and PF (p < 0.01) regions of preterm preeclampsia group as compared to control. Negative association of NGF levels in CM, CF and PM regions with baby weight and in CF, PM and PF regions with baby length was observed. NGF levels in all four regions were positively associated with systolic blood pressure. DISCUSSION: Our data indicates regional differences in levels of BDNF only in normotensive control but not in preeclampsia group. Higher NGF levels in preterm preeclampsia may be a response to increased oxidative stress. This may have implications for altered placental development in preeclampsia.

In vivo imaging of adult human hippocampal neurogenesis: progress, pitfalls and promise.

New neurons are produced within the hippocampus of the mammalian brain throughout life. Evidence from animal studies has suggested that the function of these adult-born neurons is linked to cognition and emotion. Until we are able to detect and measure levels of adult neurogenesis in living human brains-a formidable challenge for now-we cannot establish its functional importance in human health, disease and new treatment development. Current non-invasive neuroimaging modalities can provide live snapshots of the brain's structure, chemistry, activity and connectivity. This review explores whether existing macroscopic imaging methods can be used to understand the microscopic dynamics of adult hippocampal neurogenesis in living individuals. We discuss recent studies that have found correlations between neuroimaging measures of human hippocampal biology and levels of pro- or anti-neurogenic stimuli, weigh whether these correlations reflect changes in adult neurogenesis, detail the conceptual and technical limitations of these studies and elaborate on what will be needed to validate in vivo neuroimaging measures of adult neurogenesis for future investigations.

Automated drop-on-demand system with real-time gravimetric control for precise dosage formulation.

Many of the therapies for personalized medicine have few dosage options, and the successful translation of these therapies to the clinic is significantly dependent on the drug/formulation delivery platform. We have developed a lab-scale integrated system for microdosing of drug formulations with high accuracy and precision that is capable of feedback control. The designed modular drug dispensing system includes a microdispensing valve unit and is fully automated with a LabVIEW-controlled computer interface. The designed system is capable of dispensing drug droplets with volumes ranging from nanoliters to microliters with high accuracy (relative standard deviation <1%). We have determined that the system is capable of accurate dosing and in-line real-time gravimetric control.

Thermodynamic geometry, phase transitions, and the Widom line.

A microscopic characterization, based on the thermodynamic curvature R, is proposed for first-order liquid-gas phase transitions. Near the critical point, where R is proportional to the correlation volume ξ(3), we propose that R takes the same value in the coexisting phases. This proposal allows a determination of the liquid-gas coexistence curve with no use of the problematic Maxwell equal area construction. Furthermore, |R| ~ ξ(3) allows a direct determination of the Widom line in the supercritical regime. We illustrate with input from the van der Waals model and the National Institute of Standards and Technology Chemistry WebBook.

Methylphenidate for gait impairment in Parkinson disease: a randomized clinical trial.

BACKGROUND: There is a paucity of therapies for gait impairment in Parkinson disease (PD). Open-label studies have suggested improved gait after treatment with methylphenidate (MPD). OBJECTIVE: To evaluate the efficacy of MPD for the treatment of gait impairment in PD. METHODS: Twenty-seven subjects with PD and moderate gait impairment were screened for this 6-month placebo-controlled, double-blind study. Subjects were randomly assigned to MPD (maximum, up to 80 mg/day) or placebo for 12 weeks and crossed over after a 3-week washout. The primary outcome measure was change in a gait composite score (stride length + velocity) between groups at 4 and 12 weeks. Secondary outcome measures included changes in motor function, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS), Freezing of Gait Questionnaire (FOGQ), number of gait-diary freezing episodes, and measures of depression, sleepiness, and quality of life. Three-factor repeated-measures analysis of variance was used to measure changes between groups. RESULTS: Twenty-three eligible subjects with PD were randomized and 17 completed the trial. There was no change in the gait composite score or treatment or time effect for any of the variables. Treatment effect was not modified by state or study visit. Although there was a trend for reduced frequency of freezing and shuffling per diary, the FOGQ and UPDRS scores worsened in the MPD group compared to placebo. There was a marginal improvement in some measures of depression. CONCLUSIONS: MPD did not improve gait and tended to worsen measures of motor function, sleepiness, and quality of life. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence for the lack of benefit of MPD on PD-associated gait impairment. CLINICAL TRIAL REGISTRATION: NCT00526630.

Influence of age and gender on cold pressor response in Indian population.

Cold pressor test (CPT) is a simple and well documented laboratory test to evaluate the propensity for hypertension and sympathetic autonomic functions. Role of sex hormones was tested in the present study for the cold pressor response (CPR) in young adults of both sexes and in elderly population. The subjects comprised of young male (n=55), female (n=32) medical students of 17-25 years and elderly males (n=39) and females (n=25) of 50-70 years of age. The CPT was carried out in young and elderly males and females with one minute immersion of one hand in ice cold water (0-4 degrees C). Both in young males and females the absolute rise in SBP and DBP in response to Cold pressor test (CPT) was highly significant, with diastolic percent rise exceeding systolic. In comparison to young males, the females showed greater percent rise in SBP and DBP. Similarly, in elderly groups of both sexes, CPR was associated with significant absolute rise in SBP and DBP with diastolic percent rise more than systolic in males only. Both in young versus elderly males and young versus elderly females comparison yielded comparable percent rise in SBP and DBP. The SBP and DBP percent rise was again comparable between elderly males and females. The greater responsiveness to CPT in young females could be attributed to increased pain sensitivity to cold, and/or genetic and hereditary factors overwhelming the hormonal protection offered by estrogen and nitric oxide (NO).

Effect of Asparagus racemosus rhizome (Shatavari) on mammary gland and genital organs of pregnant rat.

Asparagus racemosus (AR) Willd (family Liliaceae) is commonly known as Shatavari. The alcoholic extract of its rhizome was administered orally to adult pregnant female albino rats at a dose of 30 mg/100 g body weight, daily for 15 days (days 1-15 of gestation). The macroscopic findings revealed a prominence of the mammary glands, a dilated vaginal opening and a transversely situated uterine horn in the treated group of animals. The weight of the uterine horns of the treated group was found to be significantly higher (p < 0.001) but the length was shorter (p > 0.01). Microscopic examination of the treated group showed proliferation in the lumen of the duct of mammary gland. It was obliterated due to hypertrophy of ductal and glandular cells. Hyperplasia of the glandular and muscular tissue and hypertrophy of the glandular cells were observed in the genital organs. The parenchyma of the genital organs showed abundant glycogen granules with dilated blood vessels and thickening of the epithelial lining. The oviduct in the treated group showed hypertrophied muscular wall, whereas the ovary revealed no effect of the drug. The results suggest an oestrogenic effect of Shatavari on the female mammary gland and genital organs.

Smoking women and their lung function tests.

Smoking amongst women has become significant as the number of smoking women is increasing gradually in this developing society. It affects the lungs to produce Chronic Obstructive Pulmonary Disease (COPD). Present study was conducted over 100 smoker's women and 100 non-smoker women in the age group of 30-40 Years. Three Lung Function Tests--FEVI, FVC and PEFR were employed to all smoking and non-smoking women. It was observed that all the above mentioned three parameters of lung function tests were reduced significantly among smoker women as compared to non-smoker women. These reduced parameters of lung function test among heavy smokers are suggestive of chronic obstructive lung diseases.

Measurement properties of Skindex-16: a brief quality-of-life measure for patients with skin diseases.

BACKGROUND: An accurate, sensitive, but brief quality-of-life outcomes measure is needed for studies of dermatologic care. OBJECTIVE: To construct a single-page version of Skindex (a dermatologic quality-of-life instrument) that would have two new features compared with the current 29-item version: (1) fewer items to which a majority of patients choose the same response, and (2) measurement of bother rather than frequency of patient experiences. METHODS: Random samples of patients waiting for dermatology appointments in clinics of Veterans Affairs hospitals and in private dermatology practices completed questionnaires; 692 patients responded to the parent instrument and 541 additional patients responded to the brief version. Reproducibility, internal consistency reliability, validity, and responsiveness of the brief version of Skindex were determined. RESULTS: For 16 items of the current 29-item version (55%), more than 50% of patients responded "Never." After an explicit process of item analysis and elimination, a single-page 16-item version was composed that asks patients about bother from their experiences; responses are reported as three scales, Symptoms, Emotions, and Functioning. For 6 items of the 16-item version (38%), more than 50% of patients responded "Never." Scale scores were reproducible after 72 hours (r = 0.88-0.90) and were internally reliable (Cronbach's alpha = 0.86-0.93). The instrument demonstrated both content and construct validity: Most patients' responses to an open-ended question about their skin disease was addressed by the items; patients with inflammatory dermatoses had higher scores than those with isolated lesions; and in an exploratory principal axes factor analysis with an oblique rotation, 74% of the common variance was explained by three factors that correlated with the a priori scales. Mean scale scores stayed the same or changed in the expected direction in patients who reported that their skin was the same or had improved. CONCLUSION: This brief single-page version of Skindex accurately and sensitively measures how much patients are bothered by their skin conditions.

Neuropilin-2 is required in vivo for selective axon guidance responses to secreted semaphorins.

Neuropilins are receptors for class 3 secreted semaphorins, most of which can function as potent repulsive axon guidance cues. We have generated mice with a targeted deletion in the neuropilin-2 (Npn-2) locus. Many Npn-2 mutant mice are viable into adulthood, allowing us to assess the role of Npn-2 in axon guidance events throughout neural development. Npn-2 is required for the organization and fasciculation of several cranial nerves and spinal nerves. In addition, several major fiber tracts in the brains of adult mutant mice are either severely disorganized or missing. Our results show that Npn-2 is a selective receptor for class 3 semaphorins in vivo and that Npn-1 and Npn-2 are required for development of an overlapping but distinct set of CNS and PNS projections.

Computer-integrated revision total hip replacement surgery: concept and preliminary results.

This paper describes an ongoing project to develop a computer-integrated system to assist surgeons in revision total hip replacement (RTHR) surgery. In RTHR surgery, a failing orthopedic hip implant, typically cemented, is replaced with a new one by removing the old implant, removing the cement and fitting a new implant into an enlarged canal broached in the femur. RTHR surgery is a difficult procedure fraught with technical challenges and a high incidence of complications. The goals of the computer-based system are the significant reduction of cement removal labor and time, the elimination of cortical wall penetration and femur fracture, the improved positioning and fit of the new implant resulting from precise, high-quality canal milling and the reduction of bone sacrificed to fit the new implant. Our starting points are the ROBODOC system for primary hip replacement surgery and the manual RTHR surgical protocol. We first discuss the main difficulties of computer-integrated RTHR surgery and identify key issues and possible solutions. We then describe possible system architectures and protocols for preoperative planning and intraoperative execution. We present a summary of methods and preliminary results in CT image metal artifact removal, interactive cement cut-volume definition and cement machining, anatomy-based registration using fluoroscopic X-ray images and clinical trials using an extended RTHR version of ROBODOC. We conclude with a summary of lessons learned and a discussion of current and future work.

Mirage formation in the thermal region.

Formation of a mirage in the 8-12-µm band has been observed with a high-resolution thermal camera designed and developed by us. Thermal imagery recorded under actual field conditions is presented to illustrate the mirage phenomenon. Further analysis is in progress to estimate the effect of mirages in this waveband for civil and military applications.

Cholecystectomy and a simple technique of operative cholangiography.

A simple, easily reproducible technique of operative cholangiography is described. The technique has three advantages: (a) there is no need to divide or ligate the cystic duct; (b) it demonstrates the cystic duct anatomy clearly and is particularly useful in demonstrating stones in that duct thus eliminating the hazard of the retained stone in the cystic duct stump; (c) it is possible to eliminate the problem of false positives due to air bubbles. A consecutive series of 442 cholecystectomy patients is reviewed. The overall operative mortality was 1.6 per cent; no death could be attributed to operative cholangiography. Thirty-five of 324 patients (10.8 per cent) with gallstones and no history of jaundice were shown to have unexpected abnormalities in the common bile duct.

Short-stay surgery for inguinal hernia. Clinical outcome of the Shouldice operation.

In 1970 a general surgical team on Teesside adopted the Shouldice operation for inguinal hernia together with a policy of short-stay surgery. Careful follow-up has established that repairs using the suture material of choice--stainless-steel wire--have an estimated 6-year recurrence-rate of 0.8%, statistically indistinguishable from that achieved by the highly specialised Shouldice Clinic. However, the recurrence-rate 2 years after suturing with an alternative polyester-based material is estimated at 8.1%--a figure much more in keeping with rates reported by general surgeons using traditional methods.