Lu-Ting Kuo

The biomarkers of human papillomavirus infection in tonsillar squamous cell carcinoma—molecular basis and predicting favorable outcome

Presence of human papillomavirus (HPV) in variable proportions in tonsillar squamous cell carcinoma tissues has been demonstrated by several worldwide studies. Some reports emphasized the significance of HPV in predicting a better prognosis, as well as ethnic differences between Chinese and Caucasians. In order to understand the biological role of HPV and find out clinically accessible methods to determine its prognostic significance in primary tonsillar squamous cell carcinoma, we collected 92 patients with primary tonsillar squamous cell carcinoma diagnosed or treated in National Taiwan University Hospital, for whom archival tumor tissue were available. Immunohistochemical stains of p16INK4A, high-risk HPV in situ hybridization, and nested polymerase chain reaction (PCR)-based genechips were performed to detect HPV infection and determine its genotype. Clinical data were compared with HPV infection detected by the different methods mentioned above. Real-time PCR was also performed on the HPV16-positive [HPV16(+)] lesions to understand viral integration status. The positive rates of nested PCR-based genechips, overexpression of p16INK4A, and high-risk HPV in situ hybridization were 75% (69/92), 53% (49/92), and 44% (40/92), respectively. Both overexpression of P16INK4A and high-risk HPV in situ hybridization positivity were associated with favorable prognoses (P=0.004 and 0.001, respectively) and also independent prognostic factors in multivariate analyses (P=0.01 and 0.01, respectively). The positivity of nested PCR-based genechips was not statistically significant. From our data, primary tonsillar squamous cell carcinoma with positive immunohistochemical stains of p16INK4A and/or high-risk HPV in situ hybridization is associated with a better outcome, and both methods may serve as clinically accessible markers.

Decompressive craniectomy as the primary surgical intervention for hemorrhagic contusion

The standard surgical treatment of hemorrhagic cerebral contusion is craniotomy with evacuation of the focal lesion. We assessed the safety and feasibility of performing decompressive craniectomy and duraplasty as the primary surgical intervention in this group of patients. Fifty-four consecutive patients with Glasgow Coma Scale (GCS) scores of less than or equal to 8, a frontal or temporal hemorrhagic contusion greater than 20 cm(3) in volume, and a midline shift of at least 5 mm or cisternal compression on computer tomography (CT) scan were studied. Sixteen (29.7%) underwent traditional craniotomy with hematoma evacuation, and 38 (70.4%) underwent craniectomy as the primary surgical treatment. Mortality, reoperation rate, Glasgow Outcome Scale-Extended (GOSE) scores, and length of stay in both the acute care and rehabilitation phase were compared between these two groups. Mortality (13.2% vs. 25.0%) and reoperation rate (7.9% vs. 37.5%) were lower in the craniectomy group, whereas the length of stay in both the acute care setting and the rehabilitation phase were similar between these two groups. The craniectomy group also had better GOSE score (5.55 vs. 3.56) at 6 months. Decompressive craniectomy is safe and effective as the primary surgical intervention for treatment of hemorrhagic contusion. This study also suggests that patient with hemorrhagic contusion can possibly have better outcome after craniectomy than other subgroup of patients with severe traumatic brain injury.

Early endoscope-assisted hematoma evacuation in patients with supratentorial intracerebral hemorrhage: case selection, surgical technique, and long-term results

OBJECT Currently, the effectiveness of minimally invasive evacuation of intracerebral hemorrhage (ICH) utilizing the endoscopic method is uncertain and the technique is considered investigational. The authors analyzed their experience with this method in terms of case selection, surgical technique, and long-term results. METHODS The authors performed a retrospective analysis of the clinical and radiographic data obtained in 68 patients treated with endoscope-assisted ICH evacuation. Rebleeding, morbidity, and mortality were recorded as primary end points. Hematoma evacuation rate was calculated by comparing the pre- and postoperative CT scans. Glasgow Coma Scale scores and scores on the extended Glasgow Outcome Scale (GOSE) were recorded at the 6-month postoperative follow-up. The technical aspect of this report explains details of the procedure, the instruments that are used, the methods for hemostasis, and the role of hemostatic agents in the management of intraoperative hemorrhage. The pertinent literature was reviewed and summarized. RESULTS All surgeries were performed within 12 hours of ictus, and 84% of the surgeries were performed within 4 hours. The mortality rate was 5.9%, and surgery-related morbidity occurred in 3 cases (4.4%). The hematoma evacuation rate was 93% overall-96% in the putaminal group, 86% in the thalamic group, and 98% in the subcortical group. The rebleeding rate was 1.5%. The mean operative time was 85 minutes, and the average blood loss was 56 ml. The mean GOSE score was 4.9 at 6-month follow-up. The authors acknowledge the limitations of these preliminary results in a small number of patients. CONCLUSIONS The data suggest that early endoscope-assisted ICH evacuation is safe and effective in the management of supratentorial ICH. The rebleeding, morbidity, and mortality rates are low compared with rates reported in the literature for the traditional craniotomy method. This study also showed that early and complete evacuation of ICH may lead to improved outcomes in selected patients. However, the safety and efficacy of endoscope-assisted ICH evacuation should be further investigated in a large, prospective, randomized trial.

Correlation among pathology, genetic and epigenetic profiles, and clinical outcome in oligodendroglial tumors

Recent studies have revealed a correlation between specific genetic changes, such as loss of chromosome 1p and 19q, and sensitivity of oligodendroglial neoplasm to radiotherapy and chemotherapy; epigenetic changes also play an important role in some tumors. In this retrospective study, we analyzed chromosomal alterations in 17 loci and promoter methylation status of 8 tumor‐related genes in 49 oligodendroglial tumors (29 WHO grade II and 11 WHO grade III oligodendrogliomas; 7 WHO grade II and 2 WHO grade III oligoastrocytomas) using quantitative microsatellite analysis and methylation‐specific polymerase chain reaction and correlated this information with clinical data. We also performed immunohistochemical stains for Ki‐67 and O (6)‐methyl guanine‐DNA methyl transferase. Our results showed that the frequency of deletions in regions on 1p, 9p, 10q, 17p and 19q were 71.4%, 26.5%, 6.1%, 69.4% and 89.8%, respectively. Promoter methylation was detected in p14, p15, p16, p53, p73, PTEN, MGMT and RASSF1A genes in 24.5%, 6.1%, 46.9%, 0%, 6.1%, 42.9%, 53.1% and 77.6% of tumors, respectively. Statistical analysis identified that 9p22 loss, p73 methylation and p15 methylation were independently associated with reduced overall survival, and Ki‐67 labeling index (LI) ≥ 5%, 9p22 loss, no loss of 19q, p73 methylation, p14 methylation and unmethylated MGMT predicted shorter progression‐free survival. Our findings suggest that the frequent deletion and hypermethylation of tumor‐related genes may represent a mechanism of tumor development and progression and emphasize the importance of defining new molecular markers for predicting prognosis, tumor recurrence and therapeutic response in cancer management.

Effects of systemically administered NT-3 on sensory neuron loss and nestin expression following axotomy.

Previous work has shown that administration of the neurotrophin NT‐3 intrathecally or to the proximal stump can prevent axotomy‐induced sensory neuron loss and that NT‐3 can stimulate sensory neuron differentiation in vitro. We have examined the effect of axotomy and systemic NT‐3 administration on neuronal loss, apoptosis (defined by morphology and activated caspase‐3 immunoreactivity), and nestin expression (a protein expressed by neuronal precursor cells) in dorsal root ganglia (DRG) following axotomy of the adult rat sciatic nerve. Systemic administration of 1.25 or 5 mg of NT‐3 over 1 month had no effect on the incidence of apoptotic neurons but prevented the overall loss of neurons seen at 4 weeks in vehicle‐treated animals. Nestin‐immunoreactive neurons began to appear 2 weeks after sciatic transection in untreated animals and steadily increased in incidence over the next 6 weeks. NT‐3 administration increased the number of nestin‐immunoreactive neurons at 1 month by two‐ to threefold. Nestin‐IR neurons had a mean diameter of 20.78 ± 2.5 μm and expressed the neuronal markers neurofilament 200, βIII‐tubulin, protein gene product 9.5, growth associated protein 43, trkA, and calcitonin gene‐related peptide. Our results suggest that the presence of nestin in DRG neurons after nerve injury is due to recent differentiation and that exogenous NT‐3 may prevent neuron loss by stimulating this process, rather than preventing neuron death. J. Comp. Neurol. 482:320–332, 2005.

O6-Methylguanine-DNA methyltransferase expression and prognostic value in brain metastases of lung cancers

O(6)-Methylguanine-DNA methyltransferase (MGMT) is critical for repairing pro-mutagenic DNA bases and is correlated with response to alkylating agents in cancers. Since there is great interest in pursuing the potential role of temozolomide, a novel alkylating agent, in the treatment of brain metastases, this study aimed to evaluate MGMT expression as well as its prognostic value in this devastating disease. We studied the expression and methylation status of MGMT in 86 brain metastases of lung cancers. Twenty of them had matched primary lung tumor tissues available for direct comparison. MGMT expression was assessed by immunohistochemistry (IHC); the methylation status of MGMT promoter was analyzed by nested methylation-specific PCR (MSP) and validated by quantitative real-time PCR analysis. Positive nuclear MGMT expression was detected more frequently in brain metastases as compared with primary lung cancers (83% versus 50%, P=0.004). The discordance in MGMT expression persisted in the 20 paired primary and metastatic tumors (P=0.031). MGMT promoter hypermethylation was highly correlated with loss of MGMT expression. Both univariate and multivariate analyses showed that median overall survival was significantly longer in patients with positive MGMT expression in brain metastases (16.5 versus 3.5 months, P<0.001). In conclusion, MGMT expression was enhanced in brain metastases as compared with the primary lung cancers. MGMT expression in brain metastases was significantly correlated with better survival.

Contemporary surgical outcome for skull base meningiomas

Although surgical excision of meningioma and its dural base is the most common primary management, skull base meningiomas are quite different, and contemporary management usually consists of multimodal treatment with the aim of achieving the best possible functional outcome and quality of life (QOL) for these patients. As surgery plays an important role in the treatment of skull base meningiomas, it is crucial for neurosurgeons to appreciate the surgical outcome and QOL after meningioma surgery. Outcome is usually measured for meningiomas in terms of morbidity, mortality, time to recurrence, and QOL. The extent of resection, tumor grade, proliferative markers, and tumor location are significant factors in predicting the surgical outcome. Therefore, we address each of these factors in detail in this review. Advances in recent decades in microsurgical techniques, neuroimaging modalities, neuroanesthesia, and perioperative intensive care have substantially improved the surgical outcome; therefore, most surgical outcomes discussed in this review are cited from contemporary literature (2000 to the present) in order to depict the surgical outcome of contemporary microsurgery.

Prolonged survival of a patient with cervical intramedullary glioblastoma multiforme treated with total resection, radiation therapy, and temozolomide.

We report a case of prolonged survival in a patient with cervical intramedullary glioblastoma multiforme (GBM) treated with total resection, radiotherapy, and temozolomide. A 26-year-old woman complaining of midline lower cervical pain, insidiously progressive motor weakness, paresthesia, and urinary incontinence was admitted to our institution. MRI showed an intramedullary mass lesion in the C2-C6 level, which was considered to be an ependymoma or astrocytoma. Total resection of the tumor was performed at the C2-C6 level by laminoplasty with miniplate, followed by chemoradiotherapy (focal irradiation dose of 5000, at 200 cGy per fraction for over a period of 5 weeks) with concomitant temozolomide (75 mg/m2). Histologic examination of the resected tumor confirmed GBM. The tumor consisted of a markedly pleomorphic neoplasm measuring 4.6 cm×2.6 cm×1.7 cm and characterized by necrosis, atypical mitotic figures, and endothelial proliferation. Postoperative MRI showed a centrally located, postoperative cavity at the C2-C6 level. Recurrence in the cervical spine without brain GBM metastasis was identified 25 months after operation, and temozolomide chemotherapy was reinitiated; however, the tumor progressed, and the patient died 33 months after operation. We suggest that, in addition to potential factors of tumor biology, multimodal treatment consisting of total resection of intramedullary GBM coupled with radiation therapy and temozolomide may have prolonged the survival of this patient.

Neurotrophin-3 administration alters neurotrophin, neurotrophin receptor and nestin mRNA expression in rat dorsal root ganglia following axotomy

In the months following transection of adult rat peripheral nerve some sensory neurons undergo apoptosis. Two weeks after sciatic nerve transection some neurons in the L4 and L5 dorsal root ganglia begin to show immunoreactivity for nestin, a filament protein expressed by neuronal precursors and immature neurons, which is stimulated by neurotrophin-3 (NT-3) administration. The aim of this study was to examine whether NT-3 administration could be compensating for decreased production of neurotrophins or their receptors after axotomy, and to determine the effect on nestin synthesis. The levels of mRNA in the ipsilateral and contralateral L4 and L5 dorsal root ganglia were analyzed using real-time polymerase chain reaction, 1 day, 1, 2 and 4 weeks after unilateral sciatic nerve transection and NT-3 or vehicle administration via s.c. micro-osmotic pumps. In situ hybridization was used to identify which cells and neurons expressed mRNAs of interest, and the expression of full-length trkC and p75NTR protein was investigated using immunohistochemistry. Systemic NT-3 treatment increased the expression of brain-derived neurotrophic factor, nestin, trkA, trkB and trkC mRNA in ipsilateral ganglia compared with vehicle-treated animals. Some satellite cells surrounding neurons expressed trkA and trkC mRNA and trkC immunoreactivity. NT-3 administration did not affect neurotrophin mRNA levels in the contralateral ganglia, but decreased the expression of trkA mRNA and increased the expression of trkB mRNA and p75NTR mRNA and protein. These data suggest that systemically administered NT-3 may counteract the decrease, or even increase, neurotrophin responsiveness in both ipsi- and contralateral ganglia after nerve injury.

Nighttime Sleep, Daytime Napping, and Labor Outcomes in Healthy Pregnant Women in Taiwan

We prospectively examined the associations of nighttime and daytime sleep during the third trimester of pregnancy with labor duration and risk of cesarean deliveries in a convenience sample of 120 nulliparous women who completed sleep-related questionnaires and wore wrist actigraphs for up to 7 days. Nap duration and 24-hour sleep duration were inversely associated with labor duration in women with vaginal delivery. Neither actigraphy-derived nor self-reported sleep variables were associated with type of delivery (e.g., vaginal, cesarean). Results showed a beneficial effect of sleep on labor duration and suggest that studies of sleep duration effects on labor and pregnancy outcomes require a consideration of the amount of both daytime and nighttime sleep.