MGMT-inhibitor in combination with TGF-ßRI inhibitor or CDK 4/6 inhibitor increases temozolomide sensitivity in temozolomide-resistant glioblastoma cells.

BACKGROUND: Glioblastoma (GB) remains an incurable and deadly brain malignancy that often proves resistant to upfront treatment with temozolomide. Nevertheless, temozolomide remains the most commonly prescribed FDA-approved chemotherapy for GB. The DNA repair protein methylguanine-DNA methyl transferase (MGMT) confers resistance to temozolomide. Unsurprisingly temozolomide-resistant tumors tend to possess elevated MGMT protein levels or lack inhibitory MGMT promotor methylation. In this study, cultured human temozolomide resistance GB (43RG) cells were introduced to the MGMT inhibitor O6-benzylguanine combined with temozolomide and either LY2835219 (CDK 4/6 inhibitor) or LY2157299 (TGF-ßRI inhibitor) seeking to overcome GB treatment resistance. METHODS: Treatment effects were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, western blot, cell viability, and cell cycle progression. RESULTS: Our in vitro study demonstrated that sequential treatment of O6-Benzylguanine with either LY2385219 or LY2157299-enhanced temozolomide enhanced sensitivity in MGMT+ 43RG cells. Importantly, normal human neurons and astrocytes remained impervious to the drug therapies under these conditions. Furthermore, LY2835219 has additional anti-proliferative effects on cell cycling, including induction of an RB-associated G (1) arrest via suppression of cyclin D-CDK4/6-Rb pathway. LY2157299 enhances anti-tumor effect by disrupting TGF-ß-dependent HIF-1α signaling and by activating both Smad and PI3K-AKT pathways towards transcription of S/G2 checkpoints. CONCLUSION: This study establishes the groundwork for the development of a combinatorial pharmacologic approach by using either LY2385219 or LY2157299 inhibitor plus O6-Benzylguanine to augment temozolomide response in temozolomide-resistant GB cells.

Single-visit approach of cervical cancer screening: see and treat in Indonesia.

BACKGROUND: We performed a cross-sectional study in Indonesia to evaluate the performance of a single-visit approach of cervical cancer screening, using visual inspection with acetic acid (VIA), histology and cryotherapy in low-resource settings. METHODS: Women having limited access to health-care facilities were screened by trained doctors using VIA. If the test was positive, biopsies were taken and when eligible, women were directly treated with cryotherapy. Follow-up was performed with VIA and cytology after 6 months. When cervical cancer was suspected or diagnosed, women were referred. The positivity rate, positive predictive value (PPV) and approximate specificity of the VIA test were calculated. The detection rate for cervical lesions was given. RESULTS: Screening results were completed in 22 040 women, of whom 92.7% had never been screened. Visual inspection with acetic acid was positive in 4.4%. The PPV of VIA to detect CIN I or greater and CIN II or greater was 58.7% and 29.7%, respectively. The approximate specificity was 98.1%, and the detection rate for CIN I or greater was 2.6%. CONCLUSION: The single-visit approach cervical cancer screening performed well, showing See and Treat is a promising way to reduce cervical cancer in Indonesia.

Parental acceptance of human papillomavirus (HPV) vaccination in Indonesia: a cross-sectional study.

BACKGROUND: Cervical cancer ranks the second most frequent cancer in Indonesian women. In Indonesia, human papillomavirus (HPV) vaccine acceptance has not been studied before. OBJECTIVE: To determine parental HPV vaccine acceptance in Indonesia, and factors that influence their decision. Factors include sociodemographic factors, knowledge of HPV, HPV vaccination and cervical cancer, health beliefs about cervical cancer, and attitudes towards vaccination in general. METHODS: 746 parents, with at least 1 daughter aged 0-14, were interviewed using questionnaires based on published and adjusted interviews. Interviews were done in sub district public health centers, general governmental hospitals, and via house-visits, in 5 Indonesian provinces. RESULTS: Parental HPV vaccine acceptance was 96.1%. Logistic regression revealed that age, beliefs regarding cervical cancer, and attitudes towards vaccination in general were significantly associated with HPV vaccine acceptance. Of the participants, 66.0%, 16.6%, and 15.8% had heard about cervical cancer, HPV, and HPV vaccination respectively. The mean total knowledge score was 1.91(Standard Deviation 2.31) on a 0-8 scale. Health beliefs about cervical cancer and attitudes towards vaccination in general were positive. Participants named the high cost of the vaccine, fear for side-effects, and chosen vaccination locations as possible barriers towards HPV vaccine implementation. DISCUSSION: Parental HPV vaccine acceptance is high, but knowledge about HPV and cervical cancer is low. During HPV vaccination programs, focus should not only be on providing information, but also on existing beliefs and attitudes towards cervical cancer and vaccination in general. If HPV vaccination programs were to be implemented in Indonesia, the indicated barriers should be taken into account.

Tarlov cysts: a study of 10 cases with review of the literature.

OBJECT: Tarlov or perineurial cysts are lesions of the nerve root most often found in the sacral region. Although there is agreement that asymptomatic Tarlov cysts should be followed, it is still debated whether patients with symptomatic Tarlov cysts should be treated surgically. The authors assessed the outcome and efficacy of cyst wall resection in 10 patients with symptomatic Tarlov cysts. The medical literature is reviewed, theories of origin are evaluated, and suggestions as to their cause and pathogenesis are offered. METHODS: Ten consecutive patients harboring symptomatic Tarlov cysts were treated by the senior author between 1989 and 1999. All patients were assessed for neurological deficits and pain by neurological examination and visual analog scale, respectively. Computerized tomography myelography was performed in all patients to diagnose delayed filling of the cysts. A sacral laminectomy with resection of the sacral cyst or cysts was performed in all patients. Resected material from eight of 10 patients was submitted for histopathological evaluation. Seven (70%) of 10 patients obtained complete or substantial resolution of their symptoms, with an average follow up of 31.7 months. All of these patients had Tarlov cysts larger than 1.5 cm in diameter, producing radicular pain or bladder and bowel dysfunction. Three (30%) of 10 patients experienced no significant improvement. All three patients harbored Tarlov cysts smaller than 1.5 cm in diameter, producing nonradicular pain. Histopathological examination was performed on specimens from eight of 10 patients, which demonstrated nerve fibers in 75% of cases, ganglion cells in 25% of cases, and evidence of old hemorrhage in half. CONCLUSIONS: Large cysts (> 1.5 cm) and the presence of associated radicular symptoms strongly correlate with excellent outcome. Tarlov cysts may result from increased hydrostatic pressure and trauma.

Intraoperative computed tomography for complex craniocervical operations and spinal tumor resections.

OBJECTIVE: To improve intraoperative observation of unexposed anatomic features and to verify surgical correction, a mobile computed tomographic (CT) scanner has been introduced into the operating room. To date, intraoperative CT scanning has been used predominantly for intracranial procedures. We report on the expanded use of intraoperative CT scanning for spinal surgery, because CT scanning provides excellent observation of osseous pathological features. We report on our first 17 cases, which involved complex craniocervical operations and spinal tumor resections. METHODS: The Tomoscan M CT scanner (Philips Medical Systems, Eindhoven, The Netherlands) is mobile and consists of a translatable gantry, a translatable table, and an operator's workstation. In the operating room, the patient is placed on the CT table and prepared in the usual manner. The aperture of the gantry is covered with sterile plastic drapes. The gantry is docked to the table for intraoperative CT scanning as needed for navigation and verification during surgery. Each series of scans requires approximately 15 to 20 minutes. RESULTS: Our initial experience with neurosurgical spinal cases demonstrated that the use of intraoperative CT scanning changed the course of surgery in 6 of 17 cases. CT scanning was beneficial in facilitating adequate ventral clival and craniocervical decompressions, promoting more complete tumor resections, and verifying correct graft and instrument placement before surgical closing. Other settings in which we have found the mobile CT scanner useful include the neurointerventional suite and the intensive care unit; it is also useful for radiotherapy planning. CONCLUSION: On the basis of findings for our first 17 spinal surgery cases, we conclude that intraoperative CT scanning of the spine is both feasible and beneficial for select complex spinal procedures from the craniocervical junction to the sacrum.

Lateral exit-zone stenosis and lumbar radiculopathy.

OBJECT: Hypertrophy of the superior facet of the inferior vertebra, resulting in a compression of the nerve root at the lateral foraminal exit, is a recognized cause of radicular symptoms, particularly in patients in whom previous lumbar spine surgery has failed. The lesion-specific presenting symptoms, imaging findings, and surgical treatment of this lesion, however, have received little attention. The authors prospectively studied a series of eight consecutive patients, in whom a diagnosis of lumbar stenosis at the lateral foraminal exit had been made, to elucidate the common presenting signs and symptoms of this disorder, as well as to evaluate the success of the operative treatment. METHODS: The eight patients were selected from a group of 250 consecutive patients who presented to a tertiary-care hospital and in whom a diagnosis of long-standing lumbar radiculopathy had been made. In all cases the diagnosis was confirmed by imaging studies and by intraoperative findings. The authors performed decompressive procedures on the nerve root via a medial facet-sparing approach. CONCLUSIONS: The authors conclude that this lesion presents with characteristic physical findings and on imaging studies that distinguish it from other causes of radiculopathy, and they propose a lesion-specific, facet-sparing surgical technique that has yielded excellent results.

Spondyloptotic fracture of the cervical spine in a pregnant, anemic Jehovah's Witness: technical and ethical considerations. Case report.

The authors present the case of a 15-year-old Jehovah's Witness with a hematocrit level of 19% who was 4 months pregnant and had a two-level spondyloptotic cervical spine fracture. The patient was transferred to Georgetown University Medical Center with C-5 quadriplegia 3 weeks after having been injured in an automobile collision. The neurosurgical issues in this case included addressing a rare cervical spine injury, assessing and treating a vertebral artery injury, and performing surgery on a pregnant minor with severe anemia who held strong Jehovah's Witness beliefs. An ethics consultation was convened to determine the validity of a pregnant minor's refusal to undergo transfusion on the grounds of her religious beliefs. This case illustrates the potential benefits of thorough technical and ethical evaluations and reveals how they may contribute to the delivery of care in complex neurosurgical cases. To the authors' knowledge, this is the first two-level spondyloptotic cervical spine fracture dislocation to be reported in the literature. The added complexities of the case, given that the patient was an anemic, adolescent, pregnant Jehovah's Witness who refused blood transfusion, also appear to be unprecedented.

Neuropathology of the brainstem and spinal cord in end stage rheumatoid arthritis: implications for treatment.

OBJECTIVE: To study the detailed histopathological changes in the brainstem and spinal cord in nine patients with severe end stage rheumatoid arthritis, all with clinical myelopathy and craniocervical compression. METHODS: At necropsy the sites of bony pathology were related exactly to cord segments and histological changes, and correlated with clinical and radiological findings. RESULTS: Cranial nerve and brainstem pathology was rare. In addition to the obvious craniocervical compression, there were widespread subaxial changes in the spinal cord. Pathology was localised primarily to the dorsal white matter and there was no evidence of vasculitis or ischaemic changes. CONCLUSIONS: Myelopathy in rheumatoid arthritis is probably caused by the effects of compression, stretch, and movement, not ischaemia. The additional subaxial compression may be an important component in the clinical picture, and may explain why craniocervical decompression alone may not alleviate neurological signs.

Spinal cord oedema due to venous stasis.

Venous hypertension and stagnant hypoxia in the human spinal cord are poorly understood. We report a case in which a partial Brown-Séquard syndrome resulted from obstruction of venous drainage on one side of the spinal cord. Neurological deterioration and eventual recovery paralleled the formation and clearance of oedema. The clinical and MRI findings support the contention that spinal cord injury arising as a result of obstruction to venous outflow occurs primarily in the white matter, spreading secondarily to the grey matter, and observations that obstruction of venous flow in the high cervical spinal cord results in changes in the lower cervical cord.