Adaptation to TKI Treatment Reactivates ERK Signaling in Tyrosine Kinase-Driven Leukemias and Other Malignancies.

FMS-like tyrosine kinase-3 (FLT3) tyrosine kinase inhibitors (TKI) have been tested extensively to limited benefit in acute myeloid leukemia (AML). We hypothesized that FLT3/internal tandem duplication (ITD) leukemia cells exhibit mechanisms of intrinsic signaling adaptation to TKI treatment that are associated with an incomplete response. Here, we identified reactivation of ERK signaling within hours following treatment of FLT3/ITD AML cells with selective inhibitors of FLT3. When these cells were treated with inhibitors of both FLT3 and MEK in combination, ERK reactivation was abrogated and anti-leukemia effects were more pronounced compared with either drug alone. ERK reactivation was also observed following inhibition of other tyrosine kinase-driven cancer cells, including EGFR-mutant lung cancer, HER2-amplified breast cancer, and BCR-ABL leukemia. These studies reveal an adaptive feedback mechanism in tyrosine kinase-driven cancers associated with reactivation of ERK signaling in response to targeted inhibition. Cancer Res; 77(20); 5554-63. ©2017 AACR.

All-trans retinoic acid synergizes with FLT3 inhibition to eliminate FLT3/ITD+ leukemia stem cells in vitro and in vivo.

FMS-like tyrosine kinase 3 (FLT3)-mutant acute myeloid leukemia (AML) portends a poor prognosis, and ineffective targeting of the leukemic stem cell (LSC) population remains one of several obstacles in treating this disease. All-trans retinoic acid (ATRA) has been used in several clinical trials for the treatment of nonpromyelocytic AML with limited clinical activity observed. FLT3 tyrosine kinase inhibitors (TKIs) used as monotherapy also achieve limited clinical responses and are thus far unable to affect cure rates in AML patients. We explored the efficacy of combining ATRA and FLT3 TKIs to eliminate FLT3/internal tandem duplication (ITD)(+) LSCs. Our studies reveal highly synergistic drug activity, preferentially inducing apoptosis in FLT3/ITD(+) cell lines and patient samples. Colony-forming unit assays further demonstrate decreased clonogenicity of FLT3/ITD(+) cells upon treatment with ATRA and TKI. Most importantly, the drug combination depletes FLT3/ITD(+) LSCs in a genetic mouse model of AML, and prolongs survival of leukemic mice. Furthermore, engraftment of primary FLT3/ITD(+) patient samples is reduced in mice following treatment with FLT3 TKI and ATRA in combination, with evidence of cellular differentiation occurring in vivo. Mechanistically, we provide evidence that the synergism of ATRA and FLT3 TKIs is at least in part due to the observation that FLT3 TKI treatment upregulates the antiapoptotic protein Bcl6, limiting the drug's apoptotic effect. However, cotreatment with ATRA reduces Bcl6 expression to baseline levels through suppression of interleukin-6 receptor signaling. These studies provide evidence of the potential of this drug combination to eliminate FLT3/ITD(+) LSCs and reduce the rate of relapse in AML patients with FLT3 mutations.

Identification of novel small molecule modulators of K2P18.1 two-pore potassium channel.

Two-pore domain potassium (K2P) channels are responsible for background potassium (K+) current, which is crucial for the maintenance of resting membrane potential. K2P18.1, also called TWIK-related spinal cord K+ channel (TRESK) or KCNK18, is thought to be a major contributor to background K+ currents, particularly in sensory neurons where it is abundantly expressed. Despite its critical role and potential therapeutic implication, pharmacological tools for probing K2P18.1 activity remain unavailable. Here, we report a high-throughput screen against a collection of bioactive compounds that yielded 26 inhibitors and 8 activators of K2P18.1 channel activity with more than 10-fold selectivity over the homologous channel K2P9.1. Among these modulators, the antihistamine loratadine inhibited K2P18.1 activity with IC50 of 0.49±0.23 µM and is considerably more potent than existing K2P18.1 inhibitors. Importantly, the inhibition by loratadine remains equally efficacious upon potentiation of K2P18.1 by calcium signaling. Furthermore, the loratadine effect is dependent on transmembrane residues F145 and F352, providing orthogonal evidence that the inhibition is caused by a direct compound-channel interaction. This study reveals new pharmacological modulators of K2P18.1 activity useful in dissecting native K2P18.1 function.

Inhibition of gliomagenesis and attenuation of mitotic transition by MIIP.

The migration and invasion inhibitor protein (MIIP, also known as IIp45) was discovered as a negative regulator of cell migration and invasion in glioma. Our previous studies have shown that the MIIP protein was reduced or undetectable in some tissue samples obtained from patients with glioblastoma. The significance of MIIP in gliomagenesis is unknown. In this study, we report that MIIP has an important role in the inhibition of gliomagenesis and attenuation of mitotic transition. Increased MIIP expression levels inhibited colony formation and cell growth of glioma cell lines in vitro, whereas decreased expression by specific small interfering RNA for MIIP resulted in increased cell growth. Expression of MIIP in a glial-specific mouse model blocked glioma development and progression, thus showing that MIIP is an inhibitor of gliomagenesis. Furthermore, we show that MIIP attenuates mitotic transition and results in increased mitotic catastrophe. The biochemical mechanism of MIIP in this process is associated with its regulation of anaphase-promoting complex (APC/C) activity. MIIP interacts directly with Cdc20, and the interaction of MIIP with Cdc20 inhibits APC/C-mediated degradation of cyclin B1. Thus, MIIP attenuates mitotic transition and increases mitotic catastrophe, thereby inhibiting glioma development and progression.

Fetal spina bifida repair--current trends and prospects of intrauterine neurosurgery.

Myelomeningocele is a common dysraphic defect leading to severe impairment throughout the patient's lifetime. Although surgical closure of this anomaly is usually performed in the early postnatal period, an estimated 330 cases of intrauterine repair have been performed in a few specialized centers worldwide. It was hoped prenatal intervention would improve the prognosis of affected patients, and preliminary findings suggest a reduced incidence of shunt-dependent hydrocephalus, as well as an improvement in hindbrain herniation. However, the expectations for improved neurological outcome have not been fulfilled and not all patients benefit from fetal surgery in the same way. Therefore, a multicenter randomized controlled trial was initiated in the USA to compare intrauterine with conventional postnatal care, in order to establish the procedure-related benefits and risks. The primary study endpoints include the need for shunt at 1 year of age, and fetal and infant mortality. No data from the trial will be published before the final analysis has been completed in 2008, and until then, the number of centers offering intrauterine MMC repair in the USA is limited to 3 in order to prevent the uncontrolled proliferation of new centers offering this procedure. In future, refined, risk-reduced surgical techniques and new treatment options for preterm labor and preterm rupture of the membranes are likely to reduce associated maternal and fetal risks and improve outcome, but further research will be needed.

Second-trimester intra-abdominal bowel dilation in fetuses with gastroschisis predicts neonatal bowel atresia.

OBJECTIVE: To determine in fetuses with gastroschisis the association between intra-abdominal bowel dilation in the second trimester and neonatal bowel atresia. METHODS: We reviewed ultrasound and medical records of fetuses with gastroschisis from January 1998 to August 2004. Fetuses with intra-abdominal bowel dilation in the second trimester were identified and followed into the neonatal period. RESULTS: We identified 58 mother-infant pairs showing fetal gastroschisis, with at least one prenatal ultrasound at our hospital and which were delivered there, or were transported there as newborns. Forty-eight of the 58 fetuses had no intra-abdominal bowel dilation and none of these neonates had bowel atresia. Ten of the 58 fetuses had intra-abdominal bowel dilation and all had bowel atresia at birth (P<0.0001). In eight cases in which ultrasound was performed at <25 weeks' gestation, intra-abdominal bowel dilation was already present. CONCLUSION: Intra-abdominal bowel dilation in the second trimester predicts neonatal bowel atresia in fetuses with gastroschisis.

Effects of feeding propionibacteria to dairy cows on milk yield, milk components, and reproduction.

Two weeks before parturition, 38 Holstein primiparous and multiparous cows were assigned to 1 of 3 treatment groups: control animals (n = 13) received regular total mixed rations (TMR), the low-dose group (n = 14) received the control TMR plus 6 x 10(10) cfu/cow of Propionibacterium strain P169 (P169), and the high-dose group (n = 11) received the control TMR plus 6 x 10(11) cfu/cow of P169 from -2 to 30 wk postpartum. Weekly milk samples were analyzed for percentage of milk fat, protein, lactose, and SNF, milk urea nitrogen, and somatic cell counts. Daily milk production expressed as 4% fat-corrected milk was affected by treatment and week x parity. High-dose and low-dose P169-treated cows exhibited 7.1 and 8.5% increases above controls in daily 4% fat-corrected milk, respectively. Treatment x parity and week significantly influenced percentage of milk fat, lactose, and protein, whereas treatment x parity and treatment x week influenced SNF. Ruminal propionate levels were influenced by treatment such that high-dose P169 cows had greater molar percentage of propionate than did low-dose P169 and control cows. Change in body weight postpartum was influenced by week x parity and treatment x parity such that high-dose and low-dose P169 multiparous cows exhibited a more rapid recovery of wk-1 body weight than did control multiparous cows. There was no treatment, parity, or interaction on days to first postpartum ovulation or on estrous behavior at 45 and 90 d postpartum. We concluded that P169 might have potential as an effective direct-fed microorganism to increase milk production in dairy cows.

TRAIL-induced apoptosis in gliomas is enhanced by Akt-inhibition and is independent of JNK activation.

Patients with malignant gliomas have a poor prognosis and new treatment paradigms are needed against this disease. TRAIL/Apo2L selectively induces apoptosis in malignant cells sparing normal cells and is hence of interest as a potential therapeutic agent against gliomas. To determine the factors that modulate sensitivity to TRAIL, we examined the differences in TRAIL-activated signaling pathways in glioma cells with variable sensitivities to the agent. Apoptosis in response to TRAIL was unrelated to DR5 expression or endogenous p53 status in a panel of 8 glioma cell lines. TRAIL activated the extrinsic (cleavage of caspase-8, caspase-3 and PARP) and mitochondrial apoptotic pathways and reduced FLIP levels. It also induced caspase-dependent JNK activation, which did not influence TRAIL-induced apoptosis. Because the pro-survival PI3K/Akt pathway is highly relevant to gliomas, we assessed whether Akt could protect against TRAIL-induced apoptosis. Pretreatment with SH-6, a novel Akt inhibitor, enhanced TRAIL-induced apoptosis, suggesting a protective role for Akt. Conversely, TRAIL induced caspase-dependent cleavage of Akt neutralizing its anti-apoptotic effects. These results demonstrate that TRAIL-induced apoptosis in gliomas involves both activation of death pathways and downregulation of survival pathways. Additional studies are warranted to determine the therapeutic potential of TRAIL against gliomas.

Upper level of the spina bifida defect: how good are we?

OBJECTIVE: To assess the accuracy of obstetric sonography in determining the upper level of myelomeningocele lesions. METHODS: This was a retrospective study of 171 consecutive cases of spina bifida repaired in utero. The upper level of the lesion as determined by obstetric sonography was assigned by community physicians prior to referral in the second trimester and by the authors at Vanderbilt University Medical Center during preoperative evaluation. One hundred and eleven cases had levels established by plane-film X-ray or magnetic resonance imaging after delivery and this was regarded as the gold standard. RESULTS: Of the 171 community examinations, only 29% identified a specific upper level of the lesion; our corresponding examinations specified the lesion level in all cases. Of the 111 cases that had upper levels of the lesion established by post-delivery imaging, corresponding levels were available for comparison from 35 of the community examinations and from 111 of the examinations performed at Vanderbilt. All three assigned levels were available for comparison in 35 cases. In 26% of cases, community-assigned levels agreed exactly with post-delivery levels, while 66% agreed within one level and 80% agreed within two levels. In 38% of cases, levels assigned at Vanderbilt agreed exactly with post-delivery levels, while 78% agreed within one level and 96% agreed within two levels. Upper levels of the lesion assigned at Vanderbilt were significantly more accurate overall compared with those assigned by community physicians (signed rank test [paired comparison], P = 0.048). However, comparison of lesion levels assigned at Vanderbilt in the first 50 vs. the last 61 cases revealed a significant learning effect (Fisher's exact test, P = 0.03). When comparison of lesion levels assigned by community physicians was restricted to the first 50 cases at Vanderbilt, accuracy was similar (n = 13; t-test, P = 0.16; rank sum test, 0.31). CONCLUSIONS: Community physicians were successful in assigning the upper level of the spina bifida lesion only 29% of the time. When successful, the accuracy of these determinations was similar to that of the authors at Vanderbilt. A significant learning effect was demonstrated by improved accuracy over time at Vanderbilt. A concerted continuing medical education effort is indicated to improve the imaging skills of physicians in the accurate diagnosis of the severity of spina bifida in fetuses.

Intrauterine myelomeningocele repair: effect on short-term complications of prematurity.

OBJECTIVE: To determine whether short-term complications of prematurity are affected by intrauterine myelomeningocele repair. METHODS: Medical records of the first 100 infants undergoing intrauterine myelomeningocele repair (IUMR) at the Vanderbilt University Medical Center were reviewed. Infants born at <34 weeks' gestation were identified. Two controls were identified for each IUMR infant. Controls were matched for gestational age, sex, birth weight, antenatal steroids, and mode and month of delivery. Development of respiratory distress syndrome, intraventricular hemorrhage, and chronic lung disease and days on ventilator and length of hospital stay were recorded. The results are expressed as mean values and ranges. Comparison of data between groups was performed using the Mann-Whitney U test. Categorical data were compared using the chi-square test and Fisher's exact test. p

Prenatal management of gastroschisis: the place of the amnioexchange procedure.

Gastroschisis is a malformation of the anterior abdominal wall that consists of a right paraumbilical defect with bowel loops bathed in the amniotic fluid. The survival rate is now greater than 90% and the prognosis relies mainly on morbidity attributable to bowel dysfunction. Recent research has examined gastrointestinal waste present in amniotic fluid that induces bowel toxicity and an inflammatory process. The amnioexchange procedure (changing the amniotic fluid regularly) involves a new therapeutic approach: reducing bowel injuries in the fetuses. This article shows that there is an inflammatory reaction in human gastroschisis and in the authors' model, and that the clinical and biological data plead for the practice of amnioexchange in human beings. A randomized, controlled study is now needed.

Scavenger activity of Allium psekemense B. Fedtsch.

In the present study the antioxidative properties of the bulbs, leaves and stalks of Allium psekemense B. Fedtsch were investigated. The activities of antioxidant enzymes (superoxide dismutase, catalase, peroxidase, glutathione peroxidase), quantities of malonyldialdehyde, superoxide and hydroxyl radicals and reduced glutathione and also the content of total flavonoids, chlorophylls a and b, carotenoids, vitamin C and soluble proteins were determined. The results indicate that extracts from all plant organs exhibited antioxidant activity. The highest antioxidant activity was observed in the leaves. Furthermore, the ESR signal of DMPO-OH radical adducts in the presence of the leaf phosphate buffer (pH 7) extract was reduced by 54.3%.

Phase II study of accelerated fractionation radiation therapy with carboplatin followed by PCV chemotherapy for the treatment of anaplastic gliomas.

PURPOSE: To conduct a Phase II one-arm study to evaluate the long-term efficacy and safety of accelerated fractionated radiotherapy combined with i.v. carboplatin for patients with previously untreated anaplastic gliomas. METHODS AND MATERIALS: Between 1988 and 1992, 90 patients received 1.9-2.0-Gy radiation 3 times a day with 2-h infusions of 33 g/m(2) carboplatin for two 5-day cycles separated by 2 weeks. After radiotherapy, patients received procarbazine, lomustine (CCNU), and vincristine (PCV) for 1 year or until the tumor progressed. RESULTS: Ninety patients were evaluable for analysis. Histologically, 69 had anaplastic astrocytoma; 14, anaplastic oligoastrocytoma; and 7, anaplastic oligodendroglioma. Gross total resection was performed in 20 (22%), subtotal resection in 45 (50%), and biopsy in 25 (28%); reoperation (total or subtotal resection) was performed in 50 (56%) patients. A multivariate analysis showed that a younger age (p = 0.026), Karnofsky performance score (KPS; p = 0.009), and brain necrosis (p = 0.0002) were predictive of a better survival. Results from analysis of extent of surgery (biopsy, subtotal resection, gross total resection) approached significance (p = 0.058). Radiation dose, irradiated tumor volume, and techniques used (boost and fields) were not significant variables. The median survival (MS) of all anaplastic glioma patients was 28.1 months; for anaplastic astrocytoma patients, MS was 28.7 months and 40.8 months for the combined anaplastic oligodendroglioma/oligoastrocytoma patients. Long-term survival occurred in 25% of anaplastic glioma patients who were alive 8.6 years after treatment was initiated. Treatment-induced necrosis was documented by surgery or autopsy in 19 (21%) patients; 21 (23%) had a mixed pattern of necrosis and tumor; and an additional 13 (14%) patients who did not have surgical or autopsy demonstration of predominant radiation necrosis had magnetic resonance imaging (MRI) evidence of radiation necrosis. Serious clinical neurologic deterioration and/or dementia requiring full-time caregiver attention were observed in 9 (10%) patients. CONCLUSION: When comparable selection criteria are applied, the rate of MS in this study is inferior to results attainable with current radiation and chemotherapy approaches, although the rates of long-term survival are comparable. Theoretically, patients failing therapy and dying earlier than anticipated may be because of excessive central nervous system (CNS) toxicity resulting from the combination of accelerated fractionated irradiation, intensive carboplatin chemotherapy before each radiation fraction, and postirradiation PCV chemotherapy. On the other hand, patients with treatment-induced necrosis survived significantly longer than patients who did not demonstrate MRI or histologic evidence of necrosis (MS, 106 months vs. 18-33 months).

Gestational age at intrauterine myelomeningocele repair does not influence the risk of prematurity.

OBJECTIVE: To determine the effect of gestational age at the time of intrauterine myelomeningocele repair on the duration of pregnancy and the gestational age at the time of delivery. METHODS: This study is a retrospective chart review of the maternal and neonatal medical records of all infants undergoing intrauterine myelomeningocele repair at Vanderbilt University Medical Center. Birth weight, gestational age at the time of surgery and gestational age at the time of delivery were recorded. Infants were divided into 2 groups depending on gestational age at the time of surgery, either > or = 25 weeks' gestation (group 1) or < 25 weeks (group 2). Results were expressed as medians and interquartile ranges. Statistical analysis was done using the unpaired (2-sample) t test; p values < or = 0.05 were considered significant. RESULTS: Ninety-five infants were studied. Fifty-one infants were repaired after 25 weeks' gestation (group 1) at a median gestational age of 26.3 weeks (range 25.6-27.6). Their median gestational age at delivery was 34.4 weeks (range 32.6-35.3). Forty-four infants were repaired before 25 weeks' gestation (group 2). Surgery was done at a median gestational age of 23.6 weeks (range 22.4-24.5). The median gestational age at delivery was 34 weeks (range 31.6-35.3; p = 0.88). CONCLUSION: Early intrauterine myelomeningocele repair before 25 week's gestation does not decrease the gestational age at delivery when compared with repair after 25 weeks.

Gamma-radiation sensitivity and risk of glioma.

BACKGROUND: About 9% of human cancers are brain tumors, of which 90% are gliomas. gamma-Radiation has been identified as a risk factor for brain tumors. In a previous pilot study, we found that lymphocytes from patients with glioma were more sensitive to gamma-radiation than were lymphocytes from matched control subjects. In this larger case-control study, we compared the gamma-radiation sensitivity of lymphocytes from glioma patients with those from control subjects and investigated the association between mutagen sensitivity and the risk for developing glioma. METHODS: We used a mutagen sensitivity assay (an indirect measure of DNA repair activity) to assess chromosomal damage. We gamma-irradiated (1.5 Gy) short-term lymphocyte cultures from 219 case patients with glioma and from 238 healthy control subjects frequency matched by age and sex. After irradiation, cells were cultured for 4 hours, and then Colcemid was added for 1 hour to arrest cells in mitosis. Fifty metaphases were randomly selected for each sample and scored for chromatid breaks. All statistical tests were two-sided. RESULTS: We observed a statistically significantly higher frequency of chromatid breaks per cell from case patients with glioma (mean = 0.55; 95% confidence interval [CI] = 0.50 to 0.59) than from control subjects (mean = 0.44; 95% CI = 0.41 to 0.48) (P<.001). Using 0.40 (the median number of chromatid breaks per cell in control subjects) as the cut point for defining mutagen sensitivity and adjusting for age, sex, and smoking status, we found that mutagen sensitivity was statistically significantly associated with an increased risk for glioma (odds ratio = 2.09; 95% CI = 1.43 to 3.06). When the data were divided into tertiles, the relative risk for glioma increased from the lowest tertile to the highest tertile (trend test, P<.001). CONCLUSION: gamma-Radiation-induced mutagen sensitivity of lymphocytes may be associated with an increased risk for glioma, a result that supports our earlier preliminary findings.

Cyclooxygenase-2 expression in human gliomas: prognostic significance and molecular correlations.

Cyclooxygenase (COX)-2, the inducible isoform of prostaglandin H synthase, has been implicated in the growth and progression of a variety of human cancers. Although COX-2 overexpression has been observed in human gliomas, the prognostic or clinical relevance of this overexpression has not been investigated to date. In addition, no study has analyzed the relationship between COX-2 expression and other molecular alterations in gliomas. Consequently, we examined COX-2 expression by immunohistochemistry in tumor specimens from 66 patients with low- and high-grade astrocytomas and correlated the percentage of COX-2 expression with patient survival. We also analyzed the relative importance of COX-2 expression in comparison with other clinicopathological features (age and tumor grade) and other molecular alterations commonly found in gliomas (high MIB-1 level, p53 alteration, loss of retinoblastoma (Rb) protein or p16, and high bcl-2 level). Kaplan-Meier analyses demonstrated that high COX-2 expression (>50% of cells stained positive) correlated with poor survival for the study group as a whole (P < 0.0001) and for those with glioblastoma multiforme in particular (P < 0.03). Cox regression analyses demonstrated that COX-2 expression was the strongest predictor of outcome, independent of all other variables. In addition, high COX-2 expression correlated with increasing histological grade but did not correlate with positive p53 immunostaining, bcl-2 expression, loss of p16 or retinoblastoma protein expression, or high MIB-1 expression. These findings indicate that high COX-2 expression in tumor cells is associated with clinically more aggressive gliomas and is a strong predictor of poor survival.

Adenocarcinoma of the salivary gland metastatic to the pituitary gland: case report.

OBJECTIVE AND IMPORTANCE: A case of metastasis to the pituitary gland from a ductal adenocarcinoma of the salivary gland is presented. Metastasis to this site is rare, and a salivary gland source has never previously been described. CLINICAL PRESENTATION: This patient presented with hypopituitarism, including diabetes insipidus. INTERVENTION: A craniotomy was performed to alleviate visual loss. The histological features of the sellar tumor were identical to those of a tumor removed from the parotid gland 18 months earlier. CONCLUSION: Although intrasellar tumors originating from embryonic rests of salivary gland tissue have been reported, metastasis from a malignant neoplasm arising within a true salivary gland is also possible and should not be excluded from consideration for patients in whom a salivary gland-like tumor is discovered in the sella turcica.

Lipoplasty claims experience of U.S. insurance companies.

An analysis of medical liability claims for lipoplasty (liposuction) from January of 1985 through June of 1998 compared the insurance industry experience of plastic surgeons with that of other physicians. The Data Sharing Project database of the Physician Insurers Association of America, a trade association of professional liability companies owned and operated by medical professionals that collectively insure approximately 60 percent of America's private practice physicians, was queried. Of the nearly 45,000 total entries in the database, 292 were claims for adverse events related to lipoplasty or liposuction. These raw data were stratified by physician specialty, severity of complication, practice location, patient gender, indemnity payment, and other insurance industry-relevant variables. To simplify interspecialty comparisons, we normalized the claims rate to incidents per 100 insured physicians. The indexed lipoplasty claims rate was 3.0 per 100 insured plastic surgeons and 4.1 for other surgeons; the indexed lipoplasty claims rate for nonsurgical specialists was 2.5 per 100 insured dermatologists and 2.3 for other nonsurgeons. The higher claims rate for surgeons most likely reflects the wider scope of full-service aesthetic surgery performed by surgical specialists. Nearly two-thirds of claims (65.4 percent) during the 13-year survey period were the result of hospital-based lipoplasty; 20.9 percent were office-based claims. The prevalence of hospital-based claims may be a consequence of both historical bias introduced by hospital-based specialty surgery in the early years and prudent patient safety considerations during performance of complex or prolonged procedures in more recent years.Two-thirds of the claims (67 percent) arose from informed-consent or breach-of-contract issues, far higher than the 26 percent aggregate claims norm. The mean indemnity payment was $94,534 per lipoplasty claim; claims paid against board-certified specialists averaged $83,350. Consistent with national lipoplasty demographics, 87 percent of claims were brought by women and 13 percent were brought by men. Seven fatalities (three women and four men) were noted; cause of death is not recorded in this type of database.

Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse.

BACKGROUND: Recurrent glioblastoma multiforme (GBM) is resistant to most therapeutic endeavors, with low response rates and survival rarely exceeding six months. There are no clearly established chemotherapeutic regimens and the aim of treatment is palliation with improvement in the quality of life. PATIENTS AND METHODS: We report an open-label, uncontrolled, multicenter phase II trial of temozolomide in 138 patients (intent-to-treat [ITT] population) with glioblastoma multiforme at first relapse and a Karnofsky performance status (KPS) > or = 70. One hundred twenty-eight patients were histologically confirmed with GBM or gliosarcoma (GS) by independent central review. Chemotherapy-naïve patients were treated with temozolomide 200 mg/m2/day orally for the first five days of a 28-day cycle. Patients previously treated with nitrosourea-containing adjuvant chemotherapy received 150 mg/m2/day for the first five days of a 28-day cycle. In the absence of grade 3 or 4 toxicity, patients on the 150 mg/m2 dose schedule were eligible for a 200 mg/m2 dose on the next cycle. RESULTS: The primary endpoint was six-month progression-free survival assessed with strict radiological and clinical criteria. Secondary endpoints included radiological response and Health-related Quality of Life (HQL). Progression-free survival at six months was 18% (95% confidence interval (CI): 11%-26%) for the eligible-histology population. Median progression-free survival and median overall survival were 2.1 months and 5.4 months, respectively. The six-month survival rate was 46%. The objective response rate (complete response and partial response) determined by independent central review of gadolinium-enhanced magnetic resonance imaging (MRI) scans was 8% for both the ITT and eligible-histology populations, with an additional 43% and 45% of patients, respectively, having stable disease (SD). Objectively assessed response and maintenance of a progression-free status were both associated with HQL benefits (characterized by improvements over baseline in HQL domains). Temozolomide had an acceptable safety profile, with only 9% of therapy cycles requiring a dose reduction due to thrombocytopenia. There was no evidence of cumulative hematologic toxicity. CONCLUSIONS: Temozolomide demonstrated modest clinical efficacy, with an acceptable safety profile and measurable improvement in quality of life in patients with recurrent GBM. The use of this drug should be explored further in an adjuvant setting and in combination with other agents.