Prenatal tobacco smoke exposure and risk for cognitive delays in infants born very premature.

Prenatal tobacco smoke exposure (TSE) and prematurity are independent risk factors for abnormal neurodevelopment. The objectives were to compare differences in Bayley-III cognitive, language, and motor scores at 2 years corrected age (CA) in 395 infants born very preterm (≤ 32 weeks gestation) with and without prenatal TSE. We performed multivariable linear regression analyses to examine associations between prenatal TSE and neurodevelopmental outcomes and a mediation analysis to estimate direct effects of prenatal TSE on outcomes and indirect effects through preterm birth. In total, 50 (12.6%) infants had prenatal TSE. Infants with prenatal TSE had lower mean [95% CI] Cognitive score (82.8 [78.6, 87.1]) vs. nonexposed infants (91.7 [90.1, 93.4]). In children with and without prenatal TSE, there were significant differences in mean [95% CI] Language scores (81.7 [76.0, 87.4] vs. 92.4 [90.2, 94.6], respectively) and mean [95% CI] Motor scores (86.5 [82.2, 90.7] vs. 93.4 [91.8, 95.0], respectively); scores remained significant after controlling for confounders. Preterm birth indirectly mediated 9.0% of the total effect of prenatal TSE on Cognitive score (P = NS). However, 91% of the remaining total effect was significant and attributable to TSE's direct harmful effects on cognitive development (ß = - 5.17 [95% CI - 9.97, - 0.38]). The significant association is largely due to TSE's direct effect on cognitive development and not primarily due to TSE's indirect effect on preterm birth.

GABA(A) receptor activation drives GABARAP-Nix mediated autophagy to radiation-sensitize primary and brain-metastatic lung adenocarcinoma tumors.

In non-small cell lung cancer (NSCLC) treatment, targeted therapies benefit only a subset of NSCLC, while radiotherapy responses are not durable and toxicity limits therapy. We find that a GABA(A) receptor activator, AM-101, impairs viability and clonogenicity of NSCLC primary and brain metastatic cells. Employing an ex vivo 'chip', AM-101 is as efficacious as the chemotherapeutic docetaxel, which is used with radiotherapy for advanced-stage NSCLC. In vivo , AM-101 potentiates radiation, including conferring a survival benefit to mice bearing NSCLC intracranial tumors. GABA(A) receptor activation stimulates a selective-autophagic response via multimerization of GABA(A) Receptor-Associated Protein (GABARAP), stabilization of mitochondrial receptor Nix, and utilization of ubiquitin-binding protein p62. A targeted-peptide disrupting Nix binding to GABARAP inhibits AM-101 cytotoxicity. This supports a model of GABA(A) receptor activation driving a GABARAP-Nix multimerization axis triggering autophagy. In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce toxicity. Highlights: Activating GABA(A) receptors intrinsic to lung primary and metastatic brain cancer cells triggers a cytotoxic response. GABA(A) receptor activation works as well as chemotherapeutic docetaxel in impairing lung cancer viability ex vivo . GABA(A) receptor activation increases survival of mice bearing lung metastatic brain tumors.A selective-autophagic response is stimulated by GABA(A) receptor activation that includes multimerization of GABARAP and Nix.Employing a new nanomolar affinity peptide that abrogates autophagosome formation inhibits cytotoxicity elicited by GABA(A) receptor activation.

Dynamic use of historical controls in clinical trials for rare disease research: A re-evaluation of the MILES trial.

BACKGROUND: Randomized controlled trials offer the best design for eliminating bias in estimating treatment effects but can be slow and costly in rare disease research. Additionally, an equal randomization approach may not be optimal in studies in which prior evidence of superiority of one or more treatments exist. Supplementing prospectively enrolled, concurrent controls with historical controls can reduce recruitment requirements and provide patients a higher likelihood of enrolling in a new and possibly superior treatment arm. Appropriate methods need to be employed to ensure comparability of concurrent and historical controls to minimize bias and variability in the treatment effect estimates and reduce the chances of drawing incorrect conclusions regarding treatment benefit. METHODS: MILES was a phase III placebo-controlled trial employing 1:1 randomization that led to US Food and Drug Administration approval of sirolimus for treating patients with lymphangioleiomyomatosis. We re-analyzed the MILES trial data to learn whether substituting concurrent controls with controls from a historical registry could have accelerated subject enrollment while leading to similar study conclusions. We used propensity score matching to identify exchangeable historical controls from a registry balancing the baseline characteristics of the two control groups. This allowed more new patients to be assigned to the sirolimus arm. We used trial data and simulations to estimate key outcomes under an array of alternative designs. RESULTS: Borrowing information from historical controls would have allowed the trial to enroll fewer concurrent controls while leading to the same conclusion reached in the trial. Simulations showed similar statistical performance for borrowing as for the actual trial design without producing type I error inflation and preserving power for the same study size when concurrent and historical controls are comparable. CONCLUSION: Substituting concurrent controls with propensity score-matched historical controls can allow more prospectively enrolled patients to be assigned to the active treatment and enable the trial to be conducted with smaller overall sample size, while maintaining covariate balance and study power and minimizing bias in response estimation. This approach does not fully eliminate the concern that introducing non-randomized historical controls in a trial may lead to bias in estimating treatment effects, and should be carefully considered on a case-by-case basis. Borrowing historical controls is best suited when conducting randomized controlled trials with conventional designs is challenging, as in rare disease research. High-quality data on covariates and outcomes must be available for candidate historical controls to ensure the validity of these designs. Additional precautions are needed to maintain blinding of the treatment assignment and to ensure comparability in the assessment of treatment safety.MILES ClinicalTrials.gov Number: NCT00414648.

Durvalumab plus Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: An Open-label, Nonrandomized, Phase II Clinical Trial.

PURPOSE: The efficacy of cetuximab is poor in metastatic head and neck squamous cell carcinoma (HNSCC). Cetuximab initiates natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity, with resultant recruitment of immune cells and suppression of antitumor immunity. We hypothesized that adding an immune-checkpoint inhibitor (ICI) could overcome this and lead to an enhanced antitumor response. PATIENTS AND METHODS: A phase II study of cetuximab and durvalumab in metastatic HNSCC was conducted. Eligible patients had measurable disease. Patients who had received both cetuximab and an ICI were excluded. The primary endpoint was objective response rate (ORR) by RECIST 1.1 at 6 months. RESULTS: As of April 2022, 35 patients enrolled, of whom 33 received at least 1 dose of durvalumab and were included in the response analysis. Eleven patients (33%) had received prior platinum-based chemotherapy, 10 an ICI (30%), and 1 patient (3%) cetuximab. ORR was 39% (13/33) with a median duration of response of 8.6 months [95% confidence interval (CI): 6.5-16.8]. Median progression-free and overall survivals were 5.8 months (95% CI: 3.7-14.1) and 9.6 months (95% CI: 4.8-16.3), respectively. There were 16 grade 3 treatment-related adverse events (TRAE) and one grade 4 TRAE, with no treatment-related deaths. Overall and progression-free survival did not correlate with PD-L1 status. NK cell cytotoxic activity was increased by cetuximab and further increased with the addition of durvalumab in responders. CONCLUSIONS: The combination of cetuximab and durvalumab demonstrated durable activity with a tolerable safety profile in metastatic HNSCC and warrants further investigation.

Prenatal tobacco smoke exposure and risk of brain abnormalities on magnetic resonance imaging at term in infants born very preterm.

BACKGROUND: Prenatal tobacco smoke exposure and preterm birth are associated with abnormal brain and neurodevelopmental outcomes in infants. Studies that can disentangle indirect mediating effects from direct effects of prenatal tobacco smoke exposure on sensitive early brain magnetic resonance imaging biomarkers in very preterm infants are needed. OBJECTIVE: This study aimed to determine whether prenatal tobacco smoke exposure in preterm infants posed any direct effects on magnetic resonance imaging-determined global brain abnormality score and secondary measures of brain abnormalities after removing any indirect mediating effects of preterm birth on neurostructural outcomes. STUDY DESIGN: We examined brain magnetic resonance imaging findings collected at 39 to 44 weeks postmenstrual age from a prospective cohort of 395 infants born very preterm (gestational age of ≤32 weeks). The primary outcome was global brain abnormality score, and the secondary outcomes were global efficiency of structural connectome, diffuse white matter abnormality volume, total brain tissue volume, total gray and white matter volumes, and cerebellar volume. Maternal reports of smoking during pregnancy were obtained. We performed multivariable linear regression analyses to examine the association between prenatal tobacco smoke exposure and our magnetic resonance imaging outcomes, controlling for prospectively collected confounders. Moreover, we performed a mediation analysis to estimate the direct effects of prenatal tobacco smoke exposure on brain abnormalities and any indirect effects through preterm birth. RESULTS: Overall, 12.6% of infants had prenatal tobacco smoke exposure. Infants with prenatal tobacco smoke exposure had a higher median global brain abnormality score than nonexposed infants (7 [interquartile range, 0-41] vs 5 [interquartile range, 0-34]; P≤.001); the findings remained significant (P<.001) after controlling for antenatal confounders. Global efficiency (P<.001), diffuse white matter volume (P=.037), and total brain tissue volume (P=.047) were significantly different between TSE groups in multivariable analyses. On mediation analysis, preterm birth mediated between 0% and 29% of the indirect effect of prenatal tobacco smoke exposure on several measures of brain abnormality outcomes. Thus, prenatal tobacco smoke exposure had a direct adverse effect between 71% and 100% on brain injury or abnormal development. CONCLUSION: Our study has identified multiple adverse effects of prenatal tobacco smoke exposure on sensitive and objective measures of neonatal brain injury and abnormal development; most cases seemed to be a direct effect of prenatal tobacco smoke exposure on fetal brain development. The results underscored the significant adverse neurostructural effects of prenatal tobacco smoke exposure to tobacco smoke pollutants.

Phase II Trial of Adjuvant Nivolumab Following Salvage Resection in Patients with Recurrent Squamous Cell Carcinoma of the Head and Neck.

PURPOSE: Locoregional relapse in patients with head and neck squamous cell carcinoma (HNSCC) is common, approaching 50% for some subsites despite multimodality therapy. Salvage surgery is the standard of care, but able to achieve durable control in only a minority of patients. While adjuvant radiotherapy or chemo-radiotherapy is offered to select patients, this approach can be prohibitively toxic. Given the activity and tolerability of programmed death-1 inhibitors in metastatic HNSCC, we investigated the safety and efficacy of adjuvant nivolumab after salvage surgical resection. PATIENTS AND METHODS: This was an open-label, multi-institutional phase II clinical trial (NCT03355560). Patients with recurrent, resectable HNSCC were enrolled within 6 weeks of salvage surgery. Six 28-day cycles of adjuvant nivolumab were planned. The primary endpoint was 2-year disease-free survival (DFS) more than 58%, based on an institutional historical control group of 71 patients with recurrent HNSCC who underwent salvage surgery. RESULTS: Between February 2018 and February 2020, 39 patients were enrolled. At a median follow-up of 22.1 months, 2-year DFS was 71.4% [95% confidence interval (CI), 57.8-88.1] and the 2-year overall survival (OS) was 73% (95% CI, 58-91.8). Three of 39 (8%) patients experienced grade 3 treatment-related adverse events and 3 of 39 (8%) discontinued treatment due to side effects. Ten of 39 had locoregional recurrence, while 2 of 10 also had synchronous metastatic disease. There was no difference in DFS between PD ligand-1 (PD-L1)-positive and PD-L1-negative patients. There was a nonsignificant trend toward improved DFS in patients with high tumor mutational burden (P = 0.083). CONCLUSIONS: Adjuvant nivolumab after salvage surgery in locally recurrent HNSCC is well tolerated and showed improved DFS compared with historical controls.

Phase II Clinical Trial of Neoadjuvant and Adjuvant Pembrolizumab in Resectable Local-Regionally Advanced Head and Neck Squamous Cell Carcinoma.

PURPOSE: Patients with resected, local-regionally advanced, head and neck squamous cell carcinoma (HNSCC) have a one-year disease-free survival (DFS) rate of 65%-69% despite adjuvant (chemo)radiotherapy. Neoadjuvant PD-1 immune-checkpoint blockade (ICB) has demonstrated clinical activity, but biomarkers of response and effect on survival remain unclear. PATIENTS AND METHODS: Eligible patients had resectable squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or oropharynx (p16-negative) and clinical stage T3-T4 and/or two or more nodal metastases or clinical extracapsular nodal extension (ENE). Patients received neoadjuvant pembrolizumab 200 mg 1-3 weeks prior to surgery, were stratified by absence (intermediate-risk) or presence (high-risk) of positive margins and/or ENE, and received adjuvant radiotherapy (60-66 Gy) and concurrent pembrolizumab (every 3 weeks × 6 doses). Patients with high-risk HNSCC also received weekly, concurrent cisplatin (40 mg/m2). Primary outcome was one-year DFS. Secondary endpoints were one-year overall survival (OS) and pathologic response (PR). Safety was evaluated with CTCAE v5.0. RESULTS: From February 2016 to October 2020, 92 patients enrolled. The median age was 59 years (range, 27-80), 30% were female, 86% had stage T3-T4, and 69% had ≥N2. At a median follow-up of 28 months, one-year DFS was 97% (95% CI, 71%-90%) in the intermediate-risk group and 66% (95% CI, 55%-84%) in the high-risk group. Patients with a PR had significantly improved one-year DFS relative to patients without response (93% vs. 72%, hazard ratio 0.29; 95% CI, 11%-77%). No new safety signals were identified. CONCLUSIONS: Neoadjuvant and adjuvant pembrolizumab increased one-year DFS rate in intermediate-risk, but not high-risk, HNSCC relative to historical control. PR to neoadjuvant ICB is a promising surrogate for DFS.

Residual tumor volume discriminates prognosis after surgery for neuroendocrine liver metastasis.

BACKGROUND AND OBJECTIVES: We developed objective measurements of preoperative and residual tumor volume, and debulking rate, to evaluate their prognostic value for neuroendocrine liver metastasis (NELM). METHODS: Seventy-three patients who underwent surgery for NELM were analyzed retrospectively. Indices of preoperative and postoperative residual tumor volume (pre-volume index [VI] and post-VI) were calculated as the sum of the cubes of individual tumor diameters on preoperative and postoperative imaging, respectively. The debulking rate (%) was calculated as 100 - 100 × post-VI/pre-VI. The classification and regression trees method was used to classify pre-VI and post-VI. RESULTS: Overall survival (OS) was discriminated by preoperative tumor volume (5-year OS rates, 87.8% for low pre-VI and 60.1% for high pre-VI; P = .037) and residual tumor volume (5-year OS rates, 88.1% for low post-VI and 24.8% for high post-VI; P < .001). In contrast, debulking rates of 100%, ≥90%, and <90% did not discriminate OS (5-year OS rates, 88.0%, 61.9%, and 58.9%, respectively, not significant). In multivariate analysis, residual tumor volume (high post-VI, hazard ratio, 6.40; 95% confidence interval, 1.45-32.3) was an independent prognostic factor for OS. CONCLUSIONS: Objective measurement of tumor volume demonstrates that residual tumor volume is prognostic after surgery for NELM.

PI3-kinase pathway biomarkers in oral cancer and tumor immune cells.

BACKGROUND: This study investigated the hypothesis that phosphoinositide 3-kinase (PI3-kinase) pathway dysregulation in either head and neck cancer cells and/or tumor infiltrating immune cells would influence outcomes of patients with surgically treated oral tongue squamous cell carcinomas (SCC). METHODS: We constructed tissue microarrays containing 123 oral tongue SCC samples and performed immunohistochemistry using antibodies against 7 PI3-kinase pathway markers: phosphatase and tensin homolog (PTEN), Akt, p-Akt, mammalian target of rapamycin (mTOR), phosphorylated-mammalian target of rapamycin (p-mTOR), survivin, and Ki-67). Expression levels in cancer cells or tumor infiltrating immune cells were correlated with outcomes. RESULTS: Higher levels of PTEN expression in immune cells were significantly associated with improved recurrence-free survival (heart rate (HR) = 0.45, 95% confidence interval (CI) 0.23-0.90, P = .03), and overall survival (HR = 0.34, 95% CI 0.15-0.76, P = .01) on univariate and multicovariate models. CONCLUSIONS: We identified a novel, negative prognostic role of PI3-kinase activation (as determined by PTEN loss) in oral SCC infiltrating immune cells. These findings could be relevant for clinical development of PI-3 kinase inhibitors for this disease.

Randomized phase II trial of cixutumumab alone or with cetuximab for refractory recurrent/metastatic head and neck squamous cell carcinoma.

OBJECTIVES: Cixutumumab (CIX) and cetuximab (CET) monoclonal antibodies block ligand-binding to insulin-like growth factor-1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR) respectively. The objective of this study was to assess the efficacy of CIX alone or combined with CET in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. METHODS: In this open-label phase II trial, 91 R/M HNSCC patients who progressed within 90 days of platinum-based chemotherapy, were randomized to CIX 10 mg/kg alone or with CET 500 mg/m2 every 2 weeks. Patients were stratified by prior CET use. The primary endpoint was median progression-free survival (PFS). Exploratory biomarker assessments included relevant markers on archival tumor and serial cytokine/angiogenic-factor profiles in blood. RESULTS: Forty-seven patients were treated with CIX monotherapy and 44 with combination. The median PFS was 1.9 and 2.0 months and clinical benefit rate (complete or partial responses and stable disease) was 5.9% and 15.3%, respectively. There was no exacerbation of CET toxicity by concurrent CIX exposure. Higher tumor expression of IGF-1 was associated with improved PFS in the CIX + CET arm while increased p-EGFR expression correlated with shorter PFS in patients receiving single agent CIX. Higher serum baseline levels of IGF-1 and IGFBP-3 correlated with improved PFS and overall survival (OS) in the CIX arm. Neither regimen resulted in improved PFS or OS compared to historical data with CET alone. CONCLUSION: The results of this study do not support the use of cixutumumab alone or with cetuximab in unselected patients with R/M HNSCC.

Using computed tomography scans and patient demographic data to estimate thoracic epidural space depth.

Background and Objectives. Previous studies have used varying methods to estimate the depth of the epidural space prior to placement of an epidural catheter. We aim to use computed tomography scans, patient demographics, and vertebral level to estimate the depth of the loss of resistance for placement of thoracic epidural catheters. Methods. The records of consecutive patients who received a thoracic epidural catheter were reviewed. Patient demographics, epidural placement site, and technique were collected. Preoperative computed tomography scans were reviewed to measure the skin to epidural space distance. Linear regression was used for a multivariate analysis. Results. The records of 218 patients were reviewed. The mean loss of resistance measurement was significantly larger than the mean computed tomography epidural space depth measurement by 0.79 cm (p < 0.001). Our final multivariate model, adjusted for demographic and epidural technique, showed a positive correlation between the loss of resistance and the computed tomography epidural space depth measurement (R (2) = 0.5692, p < 0.0001). Conclusions. The measured loss of resistance is positively correlated with the computed tomography epidural space depth measurement and patient demographics. For patients undergoing thoracic or abdominal surgery, estimating the loss of resistance can be a valuable tool.

A phase I/II study combining erlotinib and dasatinib for non-small cell lung cancer.

BACKGROUND: EGFR and Src are frequently activated in non-small cell lung cancer (NSCLC). In preclinical models, combining EGFR and Src inhibition has additive synergistic effects. We conducted a phase I/II trial of the combination of Src inhibitor dasatinib with EGFR inhibitor erlotinib to determine the maximum tolerated dose (MTD), pharmacokinetic drug interactions, biomarkers, and efficacy in NSCLC. METHODS: The phase I 3+3 dose-escalation study enrolled patients with solid tumors to determine the MTD. The phase II trial enrolled patients with advanced NSCLC who had undergone no previous treatments to determine progression-free survival (PFS) and response. Pharmacokinetic and tissue biomarker analyses were performed. RESULTS: MTD was 150 mg of erlotinib and 70 mg of dasatinib daily based on 12 patients treated in the phase I portion. No responses were observed in phase I. The 35 NSCLC patients treated in phase II had an overall disease control rate of 59% at 6 weeks. Five patients (15%) had partial responses; all had activating EGFR mutations. Median PFS was 3.3 months. Epithelial-mesenchymal transition markers did not correlate with outcomes. CONCLUSION: The combination of erlotinib and dasatinib is safe and feasible in NSCLC. The results of this study do not support use of this combination in molecularly unselected NSCLC.

Elevated PDGFRB gene copy number gain is prognostic for improved survival outcomes in resected malignant pleural mesothelioma.

PDGF/PDGFR pathway has been implicated in malignant pleural mesothelioma (MPM) carcinogenesis, and evidence suggests autocrine mechanisms of proliferation. We sought to evaluate the incidence of PDGFRB gene copy number gain (CNG) by fluorescence in situ hybridization and PDGFR pathway protein expression by immunohistochemistry (IHC) and correlate it to patient clinical outcome. Eighty-eight archived tumor blocks from resected MPM with full clinical information were used to perform IHC biomarkers (PDGFRα, PDGFRß, p-PDGFRß) and fluorescence in situ hybridization analysis of PDGFRB gene CNG. Spearman rank correlation, Wilcoxon rank-sum test, Kruskal-Wallis test, BLiP plots, and Kaplan-Meier method were used to analyze the biomarkers and correlation to clinical outcome. Several correlations between the IHC biomarkers were seen; however, none correlated to clinically relevant patient demographics or histology. In the CNG analysis, PDGFRB gene CNG in >10% of tumor cells had lower cytoplasmic p-PDGFRß (P=.029), while PDGFRB gene CNG in >40% of tumor cells had a higher cytoplasmic PDGFRß (P=.04). PDGFRB gene CNG status did not associate with patient demographics or tumor characteristics. PDGFR pathway IHC biomarkers did not associate with survival outcomes. However, patients with PDGFRB CNG >40% of tumor cells had improved relapse-free survival (HR 0.25 [95% CI 0.09-0.72], P=.0096) and improved overall survival (HR 0.32 [95% CI 0.11-0.89], P=.029). PDGFRB CNG >40% of MPM tumor cells is a potential prognostic biomarker for surgery and may identify a unique population of mesothelioma patients. Future validation of this biomarker in prospective trials is needed. From a retrospective review of archived tissue specimens from patients with resected malignant pleural mesothelioma tumors, we show that patients with PDGFRB CNG >40% of tumor cells had improved relapse-free survival (HR 0.25 [95% CI 0.09-0.72], P=.0096) and improved overall survival (HR 0.32 [95% CI 0.11-0.89], P=.029). PDGFRB CNG >40% of MPM tumor cells is a potential prognostic biomarker for surgery and may identify a unique population of mesothelioma patients.

Phase I trial of cisplatin, pemetrexed, and imatinib mesylate in chemonaive patients with unresectable malignant pleural mesothelioma.

BACKGROUND: We conducted a phase I trial of cisplatin/pemetrexed/imatinib mesylate, an oral platelet-derived growth factor receptor (PDGFR) inhibitor, in chemonaive patients with malignant pleural mesothelioma (MPM). METHODS: A standard 3 + 3 dose-escalating trial was used with the end points of maximum tolerated dose (MTD), response rate, survival, safety/toxicity, and tumor PDGFR levels. RESULTS: Seventeen patients with MPM were enrolled. The most common (any grade) side effects were nausea, fatigue, hypomagnesemia, and anemia. The MTD was established at dose level 3 (imatinib 600 mg) with a dose-limiting toxicity (DLT) of nausea and vomiting. The median progression-free survival (PFS) was 7.9 months and the median overall survival (OS) was 8.8 months. Patients with a sarcomatoid subtype had worse PFS (P = .01) and OS (P = .009), whereas they had a better Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 predicted for improved OS (P = .001) and PFS (P = .013). The 6 patients who completed all 6 treatment cycles had better OS (P = .006); the median PFS was 9.6 months and the OS was 22.4 months. In the translational studies, 14 patients had adequate tumor tissue that could be assessed for immunohistochemical (IHC) analysis and fluorescence in situ hybridization (FISH). Patients with higher than median p-PDGFRα IHC expression had a better OS (P = .013). When assessed as a continuous variable, higher p-PDGFRα in tumor cells correlated with an improved OS (P = .045). None of the other 4 IHC biomarkers were predictive or prognostic for survival. Twelve patients had successful PDGFRB FISH results, but none met the criteria of ≥ 4 copies of the PDGFRB gene; thus a correlation with clinical outcomes could not be done. CONCLUSION: The cisplatin/pemetrexed/imatinib mesylate combination had clinical benefit in some patients with MPM but was not well tolerated. Further investigation into alternative antiangiogenic agents, including PDGFRα inhibitors, is warranted.

Operative failure in minimally invasive parathyroidectomy utilizing an intraoperative parathyroid hormone assay.

BACKGROUND: Minimally invasive parathyroidectomy (MIP) is a targeted operation to cure primary hyperparathyroidism utilizing intraoperative parathyroid hormone monitoring (IOPTH). The purpose of this study was to quantify the operative failure of MIP. METHODS: Utilizing institutional parathyroid surgery database, demographic, operative, and biochemical data were analyzed for successful and failed MIP. Operative failure was defined as <6 months of eucalcemia after operation. RESULTS: Five hundred thirty-eight patients (96.6 %) had successful MIP with mean follow-up of 13 months, and 19 (3.4 %) had operative failure. The major cause of operative failure (11 of 19) was the result of surgeons' inability to identify all abnormal parathyroid glands. The remaining eight operative failures were the result of falsely positive IOPTH results. Eleven of 19 patients whose MIP had failed underwent a second parathyroid surgery. All but one of these patients achieved operative success, and 9 patients had missed multigland disease. Only 46 (8.3 %) of 557 patients had conversion to bilateral cervical exploration (BCE). Eighty percent of patients had more than 70 % IOPTH decrease, and all had successful operations. Patients with a marginal IOPTH decrease (50-59 %) had a treatment failure rate of 20 %. CONCLUSIONS: The most common cause of operative failure in MIP utilizing IOPTH was the result of surgeons' failure to identify all abnormal parathyroid glands. Falsely positive IOPTH is rare, and a targeted MIP utilizing IOPTH can achieve an excellent operative success rate without routine BCE. Selective BCE on patients with marginal IOPTH decrease may improve surgical outcome.

Does ifosfamide therapy improve survival of patients with dedifferentiated chondrosarcoma?

BACKGROUND: Dedifferentiated chondrosarcoma remains a significant therapeutic challenge. Studies performed to date have not identified efficacious chemotherapy regimens for this disease. QUESTIONS/PURPOSES: We sought to (1) evaluate the disease-specific survival at 2 and 5 years of patients with dedifferentiated chondrosarcoma; (2) assess the prognostic variables (both patient- and treatment-related), including the use of chemotherapy with ifosfamide, that relate to survivorship; and (3) assess specific toxicities associated with ifosfamide use. METHODS: Data from 41 patients with dedifferentiated chondrosarcoma diagnosed and treated at the University of Texas MD Anderson Cancer Center from 1986 to 2010 were analyzed for demographics, treatments, oncologic outcomes, and prognostic variables. There were 14 women and 27 men. The mean age at diagnosis was 58 years (range, 26-86 years). Seven patients presented with metastasis. Surgical resection alone was performed in 11 patients; resection and chemotherapy in 26 patients; resection and radiotherapy in two patients; and resection, chemotherapy, and radiotherapy in two patients. Ifosfamide-based regimens were used for 16 patients. In general, ifosfamide was used when the tumor was located in the trunk or if cisplatin was discontinued as a result of toxicity. Minimum followup was 8 months (median, 68 months; range, 8-281 months). Survival was estimated using Kaplan-Meier plots and analyzed by using the Cox proportional hazards model. RESULTS: Disease-specific survival rates at 2 and 5 years were 33% and 15%, respectively. Multivariate analysis revealed that treatment without ifosfamide-based chemotherapy was the only independent negative prognostic factor for disease-specific survival (hazard ratio, 0.4; 95% confidence interval, 0.17-0.92; p = 0.03). Ifosfamide was discontinued in a patient as a result of renal dysfunction and was decreased in dose in another patient who developed encephalopathy. CONCLUSIONS: In this small retrospective study, it appeared that ifosfamide-based adjuvant chemotherapy combined with surgical resection offered a treatment advantage compared with patients who did not receive the drug in patients with dedifferentiated chondrosarcoma, although disease-specific survival for patients who have this rare tumor remains dismal. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Safety of epidural analgesia in the perioperative care of patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

BACKGROUND: The perioperative coagulopathy, hemodynamic instability, and infectious complications that may occur during cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has raised concerns about the safety of epidural analgesia in patients undergoing such procedures. METHODS: We conducted a retrospective review of the perioperative anesthetic management of 215 adult patients who had undergone CRS with HIPEC with epidural analgesia. We reviewed epidural-related complications and analyzed the effect of early initiation of continuous epidural analgesia on estimated blood loss, intraoperative fluid administration, blood transfusion and vasopressor requirements, time to extubation, and length of stay. RESULTS: No epidural hematomas or abscesses were reported. Two patients (0.9 %) had delays in epidural removal because of thrombocytopenia, and two had epidural-site erythema (0.9 %). The majority of postoperative epidural-related hypotensive episodes were successfully treated with fluid boluses. Early initiation of epidural analgesic infusions (before HIPEC) was associated with significantly less surgical blood loss and fluid requirements (P = 0.005 and 0.02, respectively). Pre-HIPEC initiation of epidural infusions was not associated with a statistically significant difference in the following: volume of blood transfused, intraoperative vasopressors use, time to extubation, and length of hospital stay. CONCLUSIONS: With close hematologic monitoring and particular attention to sterility, epidural analgesia can be safely provided to patients undergoing CRS with HIPEC. Early initiation of continuous epidural infusions during surgery could lead to decreased blood loss and less intraoperative fluid administration. Prospective randomized studies are required to further investigate these potential benefits.

Infectious complications related to intrathecal drug delivery system and spinal cord stimulator system implantations at a comprehensive cancer pain center.

BACKGROUND: Intrathecal drug delivery (IDD) and spinal cord stimulator (SCS) systems are implantable devices for the management of both chronic and cancer pain. Although these therapies have favorable long-term outcomes, they are associated with occasional complications including infection. The incidence of infectious complications varies from 2 - 8% and frequently requires prolonged antibiotics and device revision or removal. Cancer patients are particularly susceptible to infectious complications because they are immunocompromised, malnourished, and receiving cytotoxic cancer-related therapies. OBJECTIVE: Determine if cancer pain patients have a higher incidence of infectious complications following implantation of IDD or SCS systems than non-cancer pain patients. STUDY DESIGN: Retrospective chart review. SETTING: Single tertiary comprehensive cancer hospital. METHODS: Following local Institutional Review Board (IRB) approval, we collected data on infectious complications for IDD and SCS systems implanted at MD Anderson Cancer Center for the treatment of cancer and chronic pain. The examined implants were performed from July 15, 2006, to July 14, 2009. In addition, we obtained data regarding patient comorbidities and perioperative risk factors to assess their impact on infectious complications. RESULTS: One hundred forty-two devices were implanted in 131 patients during the examined period. Eighty-three of the devices were IDD systems and 59 were SCS systems. Eighty percent of the patients had a diagnosis of cancer. Four infectious complications were noted with an overall infectious risk of 2.8%. The infection rate was 2.4% for IDD systems versus 3.4% for SCS systems (P = 1). All infections were at the implantable pulse generator (IPG) or pump pocket site. The rate of infection was 2.7% for cancer patients and 3.3% for non-cancer patients (P = 1). Neither the perioperative administration of prophylactic antibiotics (P = 0.4) nor the National Nosocomial Infection Surveillance (NNIS) risk level for individual patients (P = 0.15) were statistically associated with infectious complication. The mean surgical time was longer for cases with infection at 215 ± 93 minutes versus 132 ± 52 minutes for those without infection which was statistically significant (P = 0.02). LIMITATIONS: The major limitation of this study is that it was a retrospective analysis. An additional limitation is that 51(38.9%) of our patients either died or were lost to follow-up during the year following implantation which may have led to an underestimation of our infection rates. CONCLUSIONS: The experience of this tertiary cancer pain center demonstrates that infectious complications following implantation of IDD and SCS systems are relatively rare events in cancer patients. Contrary to our initial hypothesis, no difference was found in the infection rate between cancer and non-cancer patients. The main factor associated with increased risk of infectious complications was increased surgical time, indicating a need to minimize patient time in the operating room. The low infectious complication rate seen in this series compared to previous reports in non-cancer patients is likely multifactorial in nature.

Increased blood-brain barrier permeability on perfusion CT might predict malignant middle cerebral artery infarction.

BACKGROUND AND PURPOSE: Perfusion CT has been used to assess the extent of blood-brain barrier breakdown. The purpose of this study was to determine the predictive value of blood-brain barrier permeability measured using perfusion CT for development of malignant middle cerebral artery infarction requiring hemicraniectomy (HC). METHODS: We retrospectively identified patients from our stroke registry who had middle cerebral artery infarction and were evaluated with admission perfusion CT. Blood-brain barrier permeability and cerebral blood volume maps were generated and infarct volumes calculated. Clinical and radiographic characteristics were compared between those who underwent HC versus those who did not undergo HC. RESULTS: One hundred twenty-two patients (12 HC, 110 no HC) were identified. Twelve patients who underwent HC had developed edema, midline shift, or infarct expansion. Infarct permeability area, infarct cerebral blood volume area, and infarct volumes were significantly different (P < 0.018, P < 0.0211, P < 0.0001, P < 0.0014) between HC and no HC groups. Age (P = 0.03) and admission National Institutes of Health Stroke Scale (P = 0.0029) were found to be independent predictors for HC. Using logistic regression modeling, there was an association between increased infarct permeability area and HC. The OR for HC based on a 5-, 10-, 15-, or 20-cm² increase in infarct permeability area were 1.179, 1.390, 1.638, or 1.932, respectively (95% CI, 1.035 to 1.343, 1.071 to 1.804, 1.108 to 2.423, 1.146 to 3.255, respectively). CONCLUSIONS: Increased infarct permeability area is associated with an increased likelihood for undergoing HC. Because early HC for malignant middle cerebral artery infarction has been associated with better outcomes, the infarct permeability area on admission perfusion CT might be a useful tool to predict malignant middle cerebral artery infarction and need for HC.

Violence and drug use in rural teens: national prevalence estimates from the 2003 Youth Risk Behavior Survey.

OBJECTIVES: The purpose of this study was to compare national estimates of drug use and exposure to violence between rural and urban teens. METHODS: Twenty-eight dependent variables from the 2003 Youth Risk Behavior Survey were used to compare violent activities, victimization, suicidal behavior, tobacco use, alcohol use, and illegal drug use across rural, urban, and suburban teens across the country. RESULTS: Overall, rural teens were equally or more likely than both suburban and urban teens to report experiencing many measures of violent behavior, victimization, suicide behaviors, and drug use. Among all teens, nonwhites reported equal or higher rates of violent behavior and victimization than whites, but these associations disappeared within the rural-only population. CONCLUSIONS: Rural areas do not appear to provide a strongly protective effect against risk behaviors in teens and may be a risk factor in itself. Community prevention efforts should focus on reaching rural areas and segmenting program content based on need. Where white teens might benefit from an emphasis on preventing tobacco and alcohol use, nonwhite teens would benefit from an emphasis on preventing violence and victimization.