Model-based evaluation of the efficacy and safety of nivolumab once every 4 weeks across multiple tumor types.

BACKGROUND: Nivolumab 480 mg every 4 weeks (Q4W) is approved in the European Union, United States, and several other markets across multiple tumor types. Its approval was supported by quantitative efficacy/safety analyses bridging to 3 mg/kg every 2 weeks (Q2W). PATIENTS AND METHODS: The benefit-risk profile of nivolumab 480 mg Q4W relative to 3 mg/kg Q2W was evaluated using population pharmacokinetic modeling and exposure-response (E-R) analyses for safety and efficacy. Pharmacokinetic exposures were predicted for 3203 patients with melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), squamous cell carcinoma of the head and neck, urothelial carcinoma, or classical Hodgkin lymphoma. Quantitative models analyzed E-R to predict 480-mg Q4W safety across all indications and efficacy for melanoma, NSCLC, and RCC. Intratumoral receptor occupancy (RO) was predicted for parameters representing different tumor types. RESULTS: Time-averaged concentrations for 480 mg Q4W versus 3 mg/kg Q2W were higher during the first 28 days (26.8%) and similar at steady state (5.2%). The maximum concentration (Cmax) after the first dose was higher (110.4%), and the trough concentration at day 28 was lower (-22.1%) with 480 mg Q4W versus 3 mg/kg Q2W. The Cmax achieved with 480 mg Q4W was lower than the previously established safe dose of 10 mg/kg Q2W. The probability of adverse events for key safety end points was similar for 480 mg Q4W and 3 mg/kg Q2W. The predicted overall survival and objective response rates with 480 mg Q4W were comparable to 3 mg/kg Q2W. The predicted high intratumoral RO provided additional evidence to support 480 mg Q4W across tumor types. CONCLUSIONS: The benefit-risk profile for nivolumab 480 mg Q4W was predicted to be similar to that of 3 mg/kg Q2W across tumor types while providing a convenient and flexible option for patients and their caregivers.

Predictors of Surgical Outcomes of Traumatic Peripheral Nerve Injuries in Children: An Institutional Experience.

AIM: This study was undertaken to address the epidemiological characteristics, operative details, and surgical outcome of peripheral nerve injuries in children treated in a tertiary hospital in India (NIMHANS, Bangalore). MATERIALS AND METHODS: This is a retrospective study of epidemiology, operative findings, and surgical outcomes over the period of 2000-2016. Our series includes 102 children with peripheral nerve injuries of various causes. RESULTS: Intramuscular injections were the most common cause (52.9%), followed by entrapment (15.6%). The most common nerve involved was the sciatic nerve (54.9%), followed by the common peroneal nerve (13.7%), the ulnar nerve (10.8%), and the radial nerve (10.8%). Perineural adhesion was the most common intraoperative finding (74.5%), followed by a neuroma in continuity (14.7%) and gap (10.8%). Most of the children with peripheral adhesion underwent external and internal neurolysis (75.5%). Follow-up was available for 67 children. The median follow-up period was 7 months (range 3-36). The outcome was assessed according to MRC grading. Favorable functional improvement was noted in 76.1% of the children. Age less than 10 years (p = 0. 06), injury before 6 months (p = 0.03), and MRC motor grade (<3) (p = 0. 01) were positive predictive factors related to the final outcome. CONCLUSION: Early surgical intervention, age less than 10 years, and incomplete motor palsy were the best predictors of a superior functional outcome. This study can serve as a guide to determine the epidemiology, duration of intervention, and surgical outcome of traumatic peripheral nerve injuries in the pediatric population.

Brain abscess and cervical lymphadenitis due to Paraclostridium bifermentans: A report of two cases.

Paraclostridium bifermentans (current nomenclature of Clostridium bifermentans since 2016) is a gram-positive, spore-forming anaerobic bacterium. Here, we describe two cases associated with this organism. The first, primarily a case of tubercular brain abscess where P. bifermentans was isolated as part of a polymicrobial flora, following a neurosurgical procedure for the same and the second, a case of cervical lymphadenitis from which it was isolated as the sole causative agent. There are only a few reported cases of P. bifermentans in literature and these cases illustrate the widening spectrum of infections related to it.

Department of Neurosurgery, Madurai Medical College and the development of neurosurgery in South Tamil Nadu.

The development of neurosurgery in South Tamil Nadu can be traced to the Department of Neurosurgery, Madurai Medical College and Government Rajaji Hospital, Madurai, Tamil Nadu, India. The hospital was established in the year 1940 and Madurai Medical College was started in 1954. Prof. M. Natarajan founded this department in September, 1963. This department has a Neurosurgery Residency Program that is 50 years old. The establishment of this department and its growth to its present stature is documented here.

Growing Skull Fracture and the Orbitocranial Variant: Nuances of Surgical Management.

AIMS: Growing skull fracture (GSF) is a rare complication resulting from diastatic enlargement of a pediatric skull fracture. Orbitocranial GSF is a distinct variant with more complex management issues due to the displacement of the globe. This study aims to discuss surgical considerations in the management of GSF, with particular reference to orbitocranial variants. METHODS: We conducted a retrospective analysis of 7 children operated for GSFs at our institute from 2008 to 2015. RESULTS: Four boys and 3 girls were operated during this period. The mean age at initial trauma was 2 years, and most of them sustained falls. The most frequent symptoms of GSF were progressive scalp swelling and proptosis. The most common location was the orbitofrontal region. Duraplasty with cranioplasty was performed in 5 patients, while duraplasty alone was only required in 2 patients. A postoperative complication was noted in 1 patient and managed successfully. Good cosmetic results were obtained in all of the cases. CONCLUSIONS: Duraplasty is essential in the repair of GSF and should be followed by cranioplasty to prevent recurrent leptomeningeal herniation. We recommend the use of autologous bone from the surgical site for cranioplasty. Orbital roof repair is advisable for good visual and cosmetic outcome in orbitocranial variants of GSF.

The role of CT myelography in sparing the spinal cord during definitive radiotherapy in vertebral hemangioma.

INTRODUCTION: The spinal cord is poorly visualized on CT images but is well visualized in MRI images. However, implants used for spinal stabilization can produce artifacts on the MRI images which can interfere with identification of the cord. CT myelography in conjunction with CT simulation helps to clearly delineate the cord. MATERIALS AND METHODS: CT simulation was done in a patient with vertebral hemangioma. Pre- and post myelography images were obtained. Two plans were generated on pre and post myelography CT images using Eclipse™ treatment planning system (TPS) version 10.0, Varian Medical Systems, USA. The prescribed total dose to PTV was 40 Gy in 20 fractions. RESULTS: The cord was poorly visualized in the premyelogram CT images. The titanium implants used for spinal cord stabilization produced artifacts in the MRI images. Figure  Post myelogram, the contrast lit up the spinal cord. There was an overlap of 0.75 cc volume of the spinal cord with the PTV in the premyelogram images. This volume was reduced to 0 cc in the post myelogram images. There was an overlap of 5.4 cc volume of the PRV of spinal cord with the PTV in the premyelogram images which was reduced to 1 cc in the post myelogram images. The overlap region between the PTV and spinal cord received around 71% of the prescribed dose in premyelogram CT could be reduced to 0% in the post myelogram CT. The mean dose received by the overlap PRV spinal cord and PTV could be increased from 70% in the premyelogram to 92% in the post myelogram plans. CONCLUSION: CT myelogram in conjunction with CT simulation is particularly useful in cases where the tumor margin is very close to the cord and spinal implants are causing distortion of magnetic resonance images.

Subclinical respiratory dysfunction in chronic cervical cord compression: a pulmonary function test correlation.

OBJECTIVE Respiratory abnormalities are well documented in acute spinal cord injury; however, the literature available for respiratory dysfunction in chronic compressive myelopathy (CCM) is limited. Respiratory dysfunction in CCM is often subtle and subclinical. The authors studied the pattern of respiratory dysfunction in patients with chronic cord compression by using spirometry, and the clinical and surgical implications of this dysfunction. In this study they also attempted to address the postoperative respiratory function in these patients. METHODS A prospective study was done in 30 patients in whom cervical CCM due to either cervical spondylosis or ossification of the posterior longitudinal ligament (OPLL) was diagnosed. Thirty age-matched healthy volunteers were recruited as controls. None of the patients included in the study had any symptoms or signs of respiratory dysfunction. After clinical and radiological diagnosis, all patients underwent pulmonary function tests (PFTs) performed using a standardized Spirometry Kit Micro before and after surgery. The data were analyzed using Statistical Software SPSS version 13.0. Comparison between the 2 groups was done using the Student t-test. The Pearson correlation coefficient was used for PFT results and Nurick classification scores. A p value < 0.05 was considered significant. RESULTS Cervical spondylotic myelopathy (prolapsed intervertebral disc) was the predominant cause of compression (n = 21, 70%) followed by OPLL (n = 9, 30%). The average patient age was 45.06 years. Degenerative cervical spine disease has a relatively younger onset in the Indian population. The majority of the patients (n = 28, 93.3%) had compression at or above the C-5 level. Ten patients (33.3%) underwent an anterior approach and discectomy, 11 patients (36.7%) underwent decompressive laminectomy, and the remaining 9 underwent either corpectomy with fusion or laminoplasty. The mean preoperative forced vital capacity (FVC) (65%) of the patients was significantly lower than that of the controls (88%) (p < 0.001). The mean postoperative FVC (73.7%) in the patients showed significant improvement compared with the preoperative values (p = 0.003). The mean postoperative FVC was still significantly lower than the control value (p = 0.002). The mean preoperative forced expiratory volume in 1 second (FEV1) (72%) of the patients was significantly lower than that of the controls (96%) (p < 0.001). The mean postoperative FEV1 (75.3%) in the cases showed no significant improvement compared with the preoperative values (p = 0.212). The mean postoperative FEV1 was still significantly lower than the control value (p < 0.001). The mean postoperative FEV1/FVC was not significantly different from the control value (p = 0.204). The mean postoperative peak expiratory flow rate was significantly lower than the control value (p = 0.01). The mean postoperative maximal voluntary ventilation was still significantly lower than the control value (p < 0.001). On correlating the FVC and Nurick scores using the Pearson correlation coefficient, a negative correlation was found. CONCLUSIONS There is subclinical respiratory dysfunction and significant impairment of various lung capacities in patients with CCM. The FVC showed significant improvement postoperatively. Respiratory function needs to be evaluated and monitored to avoid potential respiratory complications.

Multifocal spinal malignant peripheral nerve sheath tumor in an immunocompromised individual: case report and review of literature.

PURPOSE: Primary intraosseous spinal malignant peripheral nerve sheath tumor (MPNST) is exceedingly rare. MPNST with multifocal origin has been described to occur in the extremities. Such a lesion has not been described to occur in the spine. We describe a case of multifocal spinal MPNST and to review the literature relevant to this rare entity and its management. METHODS: A 40-year-old immunodeficient patient presented with rapidly progressive paraparesis and mid back ache. RESULTS: Despite aggressive surgical decompression, he developed multiple metastases 3 months after surgery. However, he remained stable for 1 year without any adjuvant therapy. Presently, he has received palliative radiotherapy for spinal recurrence and cerebral metastasis. CONCLUSION: Multifocal spinal MPNST is a rare lesion. In this instance, the multifocality of the disease and its odd location could be attributed to the immunodeficiency state. The prolonged survival could be due to an improvement in his immune status due to HAART.

Alleles of the major histocompatibility complex play a role in the pathogenesis of pancreatic acinar atrophy in dogs.

Exocrine pancreatic insufficiency (EPI) is a disease wherein pancreatic acinar cells fail to synthesize and secrete sufficient amounts of digestive enzymes for normal digestion of food. EPI affects many dog breeds, with a dramatically higher prevalence in the German shepherd dog (GSD) population. In this breed and perhaps others, EPI most often results from degeneration of the acinar cells of the pancreas, a hereditary disorder termed pancreatic acinar atrophy (PAA). Evidence of lymphocytic infiltration indicates that PAA is an autoimmune disease, but the genetic etiology remains unclear. Data from global gene expression and single nucleotide polymorphism profiles in the GSD suggest the involvement of the major histocompatibility complex [MHC; dog leukocyte antigen (DLA)]. To determine if alleles of the MHC influence development of EPI, genotyping of polymorphic class I (DLA-88) and II loci (DLA-DRB1, DLA-DQA1, and DLA-DQB1) was carried out for 70 affected and 63 control GSDs, and four-locus haplotypes were determined. One haplotype containing a novel allele of DLA-88 is very highly associated with EPI (OR > 17; P = 0.000125), while two haplotypes were found to confer protection from EPI (P = 0.00087 and 0.0115). Described herein is the genotyping of MHC class I and II loci in a GSD cohort, establishment of four-locus haplotypes, and association of alleles/haplotypes with EPI.

In vitro anticandidal evaluation of novel highly functionalized bis cyclohexenone ethyl carboxylates.

OBJECTIVES: Novel highly functionalized bis cyclohexenone ethyl carboxylates 7-12 were designed, synthesized and their structures were elucidated by their elemental analysis, MS, FT-IR, one-dimensional 1H, and 13C NMR spectroscopic data. MATERIALS AND METHODS: All the synthesized compounds 7-12 were tested for their in vitro antifungal activities against Candida sp. namely Candida albicans, Candida tropicalis, Candida glabrata, Candida parapsilosis, Candida dubliniensis and Candida krusei. RESULTS: A close inspection of the in vitro anticandidal activity profile in differently electron withdrawing (-F, -Cl, and -Br) functional group and electron donating (CH3 and OCH3) substituted phenyl rings of novel highly functionalized bis cyclohexenone ethyl carboxylates 7-12 exerted strong anticandidal activity against all the tested Candida species. All the synthesized compounds 7-12 exhibited MIC value in the range of 6.25-200 µg/mL against all the tested Candida (C.) species. CONCLUSIONS: Compound 8 against C. albicans, 9,11 against C. glabrata, 8,10 against C. parapsilosis, 7,9 against C. dubliniensis, 8,10 against C. krusei exhibited excellent anticandidal activity at a MIC value of 6.25 µg/mL. Likewise compound 7, 9-11 against C. albicans, 8, 9, 11 against C. tropicalis, 8 against C. glabrata, 9 against C. parapsilosis, 10 against C. dubliniensis, 9 against C. krusei revealed superior activity at a MIC value of 12.5 µg/mL.

Non-infantile desmoplastic cerebellar ganglioglioma in a patient with multiple congenital anomalies: a rare association.

Numerous syndromes with craniofacial, cardiac, cutaneous and vascular anomalies have been described in the literature. Here we report on a 9-year-old girl who was diagnosed as having a clavicular arteriovenous malformation with limb enlargement, an axillary port wine stain and macrocephaly with frontal bossing. She was investigated for enlarged head size; although she did not have hydrocephalus as initially suspected, she was found to have a right cerebellar lesion. This was excised and the pathology report was diagnostic of desmoplastic ganglioglioma. The posterior fossa is a very rare location for gangliogliomas. This was a desmoplastic variant that is only encountered in infants. Thus, the location and the pathology made the tumour rare. In addition, the cranio-vasculo-cutaneous lesions made this previously unreported association noteworthy.

Opportunistic Fonsecaea pedrosoi brain abscess in a patient with non-cirrhotic portal fibrosis-induced hypersplenism--a novel association.

Non-cirrhotic portal fibrosis, a common cause of splenomegaly in tropical countries, can lead to hypersplenism and pancytopenia. Hypersplenism in this setting has not been associated with opportunistic infections. We describe a patient with hypersplenism secondary to non-cirrhotic portal fibrosis who developed a Fonsecaea pedrosoi brain abscess and succumbed to the illness despite aggressive management.

Resource utilization and convalescent care cost in neonatal opioid withdrawal syndrome.

BACKGROUND: Neonatal opioid withdrawal syndrome (NOWS) is a growing public health problem associated with complex and prolonged medical care and a significant resource utilization burden. The objective of this study was to compare the cost of different convalescent care settings for infants with NOWS. METHODS: Retrospective comparison study of infants with NOWS discharged directly from NICU, transferred to an acute care pediatric floor (PPCU) or rehabilitation hospital (PRH). Primary outcomes were length of stay (LOS) and cost of stay (COS). RESULTS: Infants had 1.3 (95% CI: 1.1,1.6) times and 2.5 (95% CI: 2.1,3.1) times significantly longer mean LOS for PPCU and RH discharges compared to NICU discharges. NICU discharged infants had the lowest mean COS ($25,745.00) and PRH the highest ($60,528.00), despite PRH having a lower cost per day. PRH discharged infants had higher rates of methadone and benzodiazepine and less buprenorphine exposure than NICU/PPCU discharged. Infants born to mothers on marijuana and buprenorphine had a 28% lower mean COS compared to unexposed infants. Median treatment cumulative morphine doses were six-fold higher for PRH than NICU discharge. CONCLUSIONS: Infants transferred to convalescence care facilities had longer and more costly admissions and received more medication. However, there may be a role for earlier transfer of a subset of infants at-risk for longer LOS as those exposed to methadone and/or benzodiazepines. Further studies exploring differences in resource utilization, convalescent care delivery and cost expenditure are recommended.

Trigeminal Somatosensory Evoked Potentials During Neurosurgical Procedures Using Electrical Stimulation of the Lips Under General Anesthesia.

Background Intraoperative neurophysiology monitoring is rapidly evolving with the advent of newer modalities. Long latency sensory evoked potentials from the trigeminal nerve distribution have rarely been demonstrated during neurosurgical procedures. Trigeminal sensory evoked potential (TSEP) can be used to prevent nerve injury during surgical procedures, such as those for trigeminal neuralgia and tumors involving the trigeminal nerve and pathway. Methodology We attempted to record TSEP from 12 subjects who underwent various neurosurgical procedures with low doses of inhalational anesthetic agents. We stimulated the upper and lower lip and recorded from C6 and Fz locations. We used 14-17 mA current stimuli with a pulse width of 50-150 microseconds and a stimulation rate of 2.1 Hz. Results We could obtain a clear, reproducible TSEP response in two out of 12 subjects. We observed a TSEP waveform with negative peaks at 13 and 27 milliseconds and a positive wave at around 19 milliseconds. Conclusions The TSEP produced by the electrical stimulation of the upper and lower lip can be detected from the scalp C5, C6, and Fz area even during neurosurgical procedures, even if inhalational anesthesia was used at induction, but only in a small proportion of cases. It appeared to reflect the activity of trigeminal cortical response. Avoiding the notch filter and turning off the inhalational agents are essential for a good response.

An Analysis of Eosinophil- and Basophil-Based Indices in Patients with Glioblastoma and their Correlation with Survival.

BACKGROUND: Glioblastoma (GBM) is the most frequently diagnosed malignant brain tumor in adults. GBM is usually lethal within 24 months of diagnosis, despite aggressive multimodality treatment. Although it has been established that cancer-related inflammation is associated with worse outcomes, the role of eosinophils, basophils, atopy, and allergy in glioma biology is only gradually being delineated. In this study, we aimed to examine if eosinophil-based and basophil-based indices were altered in patients with GBM compared with healthy controls. We also aimed to study if there was any correlation between these indices and patient-related and tumor-related factors and survival. METHODS: This study was a retrospective analysis of prospectively maintained databases. Data pertaining to patient-related and tumor-related factors, hemograms, and survival data were obtained from the electronic medical records of selected patients. Correlations between eosinophil-based and basophil-based indices and these factors were studied, as was the association with overall survival. RESULTS: All the indices were altered in patients with GBM compared with normal healthy controls. The absolute eosinophil count was higher and the neutrophils/eosinophils ratio was lower in the better prognosis groups: those with better performance status; those without features of increased intracranial pressure or altered sensorium at presentation; those with ATRX-retained tumors that did not overexpress p53; and in the long-term survivors. The total lymphocyte count/basophils ratio and the absolute eosinophil count both independently predicted survival in a multivariate analysis. CONCLUSIONS: The absolute eosinophil count was consistently higher in the better prognosis groups and is likely to be incorporated into prognostic models for GBM.

Idiopathic intraventricular aneurysm presenting with intraventricular hemorrhage: case report and review of the literature.

Intraventricular hemorrhage (IVH) is a relatively commonly encountered problem in neurosurgical practice. The underlying causes could include hypertension, arteriovenous malformations (AVM), angiomas, trauma, tumors, aneurysms and moyamoya disease. Truly idiopathic intraventricular aneurysms (IVA) are rare. A high index of suspicion needs to be maintained since, with the appropriate treatment, the outcome is generally good. We report the case of a 14-year-old boy who presented with sudden onset headache and vomiting. CT angiogram pointed to the possibility of an IVA. This was confirmed by MRI with three-dimensional constructive interference in steady state (CISS-3D) sequences and digital subtraction angiography. The patient underwent microsurgical excision of the aneurysm and is doing well on follow-up. Idiopathic IVA can present with IVH at any age. MRI with CISS-3D and MR angiography would be the imaging modality of choice since it can also rule out other causes of intraventricular bleeding such as tumors and AVM. These lesions could be managed effectively by microsurgical excision/clipping. The necessity of investigating every patient who presents with IVH is debatable.

A facile microwave assisted green chemical synthesis of novel piperidino 2-thioxoimidazolidin-4-ones and their in vitro microbiological evaluation.

A series of novel hybrid heterocyclic compounds, 3-(3-alkyl-2,6-diarylpiperin-4-ylidene)-2-thioxoimidazolidin-4-ones were synthesised and a comparative study was also carried out under microwave irradiation. The synthesised compounds were characterised by their melting points, elemental analysis, MS, FT-IR, one-dimensional NMR (1H, D(2)O exchanged 1H and (13)C), two dimensional HOMOCOSY and NOESY spectroscopic data. All the synthesised title compounds were screened for their in vitro antibacterial and antifungal activity against clinically isolated strains namely B. subtilis, M. luteus, S. typhii, S. paratyphii B, S. felxneri, P. vulgaris, A. niger, Mucor, Rhizopus and M. gypsuem and the results were discussed.