A phase I trial of concurrent sorafenib and stereotactic radiosurgery for patients with brain metastases.

We hypothesized that sorafenib (BAY 43-9006), an oral multi-kinase inhibitor, used in combination with SRS will improve overall intracranial control. This Phase I study assesses the safety, tolerability, and maximal tolerated dose of sorafenib administered with SRS to treat 1-4 brain metastases. This was an open label phase I dose escalation study with an expansion cohort. Eligible adults had 1-4 brain metastases from solid malignancies. Sorafenib was begun 5-7 days prior to SRS and continued for 14 days thereafter. Dose escalation of sorafenib was conducted via a "3 + 3" dose escalation design. Dose limiting toxicities (DLT) were determined 1 month after SRS and defined as ≥grade 3 neurologic toxicities. Twenty-three patients were enrolled. There were no DLTs at dose level 1 (400 mg per day) or dose level 2 (400 mg twice per day). An expansion cohort of 17 patients was treated at dose level 2. There were six grade 3 toxicities: hypertension (n = 2), rash (n = 1), lymphopenia (n = 1), hypokalemia (n = 1), fatigue (n = 1) and hand-foot syndrome (n = 1). All of these were attributable to sorafenib and not to the combination with SRS. The median time to CNS progression was 10 months, 1 year CNS progression-free survival was 46%, the median overall survival was 11.6 months and the 1 year overall survival was 46%. The use of sorafenib concurrent with SRS for the treatment of 1-4 brain metastases is safe and well tolerated at 400 mg twice a day. Our recommended phase II dose of concurrent sorafenib with SRS would be 400 mg twice daily.

Measurement of products of docosahexaenoic acid peroxidation, neuroprostanes, and neurofurans.

Free radicals derived primarily from oxygen have been implicated in the pathophysiology of a wide variety of human diseases. Quantification of products of free radical damage in biological systems is necessary to understand the role of free radicals in disease states. Measures of lipid peroxidation are often used to quantitate oxidative damage though many of these measures have inherent problems with sensitivity and specificity especially when used to quantitate in vivo oxidative injury. The discovery of the F(2)-isoprostanes (F(2)-IsoPs), prostaglandin F(2)-like compounds derived by the free radical peroxidation of arachidonic acid (AA, C20:4, omega-6) has largely overcome these limitations. The measurement of the F(2)-IsoPs has been shown to be one of the most accurate approaches to quantifying oxidative damage in vivo. We have extended our studies of lipid peroxidation and the F(2)-IsoPs to docosahexaenoic acid (DHA, C22:6, omega-3) and its peroxidation products. We have found that DHA oxidizes both in vitro and in vivo to form F(2)-IsoP-like compounds termed F(4)-neuroprostanes (F(4)-NPs). DHA is specifically enriched in neuronal membranes making the F(4)-NPs sensitive and specific markers of neuronal oxidative damage. Adapting the methodology used to quantitate the F(2)-IsoPs, we utilize stable isotope dilution, negative ion chemical ionization, gas chromatography mass spectrometry (GC/MS) to quantitate the F(4)-NPs with a limit of detection in the low picomolar range. Methods have been developed to quantitate both the F(4)-NPs and the neurofurans (NFs), DHA derived peroxidation products containing a substituted tetrahydrofuran ring, in brain tissue and cerebrospinal fluid. This review outlines in detail proper sample handling, extraction and hydrolysis of the F(4)-NPs and NFs from tissue membrane phospholipids or biological fluids, and purification and derivatization of the compounds for analysis by GC/MS.

The Refusal of Palliative Radiation in Metastatic Non-Small Cell Lung Cancer and Its Prognostic Implications.

CONTEXT: Patients with metastatic non-small cell lung cancer (NSCLC) have limited survival. Population studies have evaluated the impact of radiation refusal in the curative setting; however, no data exist concerning the prognostic impact of radiation refusal in the palliative care setting. OBJECTIVES: To investigate the patterns of radiation refusal in newly diagnosed patients with metastatic NSCLC. METHODS: Patients with Stage IV NSCLC diagnosed between 1988 and 2010 were identified in the Surveillance, Epidemiology, and End Results database. Univariate and multivariate analyses were used to identify predictors for refusal of radiation and the impact of radiation and refusal on survival in the palliative setting. RESULTS: A total of 285,641 patients were initially included in the analysis. Palliative radiation was recommended in 42% and refused by 3.1% of patients. Refusal rates remained consistent across included years of study. On multivariate analysis, older, nonblack/nonwhite, unmarried females were more likely to refuse radiation (P < 0.001 in all cases). Median survival for patients refusing radiation was three months vs. five months for those receiving radiation and two months for those whom radiation was not recommended. CONCLUSION: Patients with metastatic NSCLC who refuse recommended palliative radiation have a poor survival. Radiation refusal or the recommendation against treatment can serve as a trigger for integrating palliative care services sooner and contributes greatly to prognostic awareness. Further investigation into this survival difference and the factors behind refusal are warranted.

From whole brain to hospice: patterns of care in radiation oncology.

OBJECTIVES: The development of brain metastases is a common cause of morbidity and mortality in cancer patients. Limited life expectancy is well established once a patient requires whole-brain radiotherapy (WBRT). There is emerging evidence demonstrating the value of involving palliative care services alongside traditional treatments. However, data regarding the utilization of these services in patients requiring WBRT remain unexplored. METHODS: Patients with histologic or radiographic evidence of brain metastases treated with WBRT alone between July 2010 and June 2012 were reviewed retrospectively. Patient demographics, the number of hospital admissions in the last 6 months of life, survival, and referrals to palliative care services were evaluated. RESULTS: Ninety-eight patients were diagnosed with brain metastases and treated with WBRT alone. The median overall survival following WBRT was 80 days. Twenty-eight of the patients presented to the emergency department ≥2 times in the last 6 months of life. Sixty-eight percent of patients were referred to palliative care. Of those referrals, 57% were during an inpatient hospitalization. The median survival from palliative care referral to death was 27 days. CONCLUSIONS: Patients with brain metastasis requiring WBRT have a predictable dying trajectory. These patients are likely to have a high symptom burden and would benefit from palliative care. Timely palliative care referrals in this population remain inadequate and classically follow a hospital admission. Referrals continued to be late in the dying process and the recommendation for WBRT can be used as an independent marker for initiating end-of-life discussions and involving palliative care.

Locally advanced head and neck cancer.

Treatment of locally advanced head and neck squamous cell carcinomas requires a multidisciplinary approach to be able to offer patients definitive therapy while aiming to preserve organ function and minimize acute and long-term toxicities. Advances in surgical techniques will be reviewed for both primary sites and the neck and also in the salvage settings. Recent data on concurrent versus sequential chemoradiotherapy in these patients will be reviewed, with emphasis on identification of appropriate patients for sequential chemoradiotherapy. Finally, advances in modern radiotherapy modalities that have resulted in improved dosimetry and quality of life following treatment will be reviewed.

A workshop on leadership for MD/PhD students.

Success in academic medicine requires scientific and clinical aptitude and the ability to lead a team effectively. Although combined MD/PhD training programs invest considerably in the former, they often do not provide structured educational opportunities in leadership, especially as applied to investigative medicine. To fill a critical knowledge gap in physician-scientist training, the Vanderbilt Medical Scientist Training Program (MSTP) developed a biennial two-day workshop in investigative leadership. MSTP students worked in partnership with content experts to develop a case-based curriculum and deliver the material. In its initial three offerings in 2006, 2008, and 2010, the workshop was judged by MSTP student attendees to be highly effective. The Vanderbilt MSTP Leadership Workshop offers a blueprint for collaborative student-faculty interactions in curriculum design and a new educational modality for physician-scientist training.

A potential route to neuroprostanes and isoprostanes: preparation of the four enantiomerically pure diastereomers of 13-F4t-neuroP.

We report a potential synthetic route to the isoprostanes and the neuroprostanes that could allow ready access to each of the enantiomerically pure diastereomers of the several regioisomers of these important human metabolites. The key transformation in the synthesis is a highly diastereoselective thermal intramolecular ene reaction. A critical observation is that the four enantiomerically pure diastereomers of an intermediate acetylenic ester are easily separated from one another. Each of these four has been carried on to a different enantiomerically pure diastereomer of 13-F4t-neuroprostane.

Reaction of aflatoxin B(1) oxidation products with lysine.

Aflatoxin (AF) B(1) exo-8,9-epoxide hydrolysis yields AFB(1) dihydrodiol, which undergoes base-catalyzed rearrangement to, and is in equilibrium with, AFB(1) dialdehyde. We investigated the reaction of AFB(1) dialdehyde with albumin to generate a Lys adduct, previously characterized by others [Sabbioni, G., Skipper, P. L., Büchi, G., and Tannenbaum, S. R. (1987) Carcinogenesis8, 819-824; Sabbioni, G. (1990) Chem.-Biol. Interact. 75, 1-15]. Pronase digestion of bovine albumin serum treated with AFB(1) dialdehyde and HPLC yielded the adduct, identified by its characteristic UV and mass spectra. The structure of the Lys-AFB(1) dialdehyde adduct is concluded to be (S)-alpha-amino-2,3-dihydro-2-oxo-4-(1,2,3,4-tetrahydro-7-hydroxy-9-methoxy-3,4-dioxocyclopenta[c][1]benzopyran-6-yl)-1H-pyrrole-1-hexanoic acid, structure B of the former paper and 8 of the latter, based on work with the methylamine adduct described in the following paper in this issue [Guengerich, F. P., Voehler, M., Williams, K. M., Deng, Z., and Harris, T. M. (2002) Chem. Res. Toxicol. 15, 793-798]. The time course of product formation at varying concentrations of AFB(1) dialdehyde could be described by complexation with albumin with a K(d) of 1.5 mM and a first-order reaction rate with the N6-amino group of Lys of 0.033 min(-)(1). The reaction of AFB(1) dialdehyde with N(2)-acetylLys was monitored by UV spectroscopy and yielded a final spectrum similar to that of the described Lys adduct. Kinetic analysis of the changes at pH 7.2 was best described with a scheme involving equilibrium of the dialdehyde with dihydrodiol and a rate-limiting reaction of AFB(1) dialdehyde with the N6 atom of N(2)-acetylLys, with an apparent second-order rate constant of 2.6 x 10(3) M(-)(1) min(-)(1), followed by putative carbinolamine formation and rearrangement, collectively described by a first-order rate constant of 7.6 min(-)(1). Competition experiments with the hydrolysis of AFB(1) exo-8,9-epoxide indicate that N2-acetylLys also reacts with the epoxide at pH 7.2 (k = 350 M(-)(1) min(-)(1)) and 9.5 (k = 1.8 x 10(3) M(-)(1) min(-)(1)). This reaction might contribute to the formation of protein Lys adducts, depending upon the local concentration of free or protein Lys. Mass spectral analysis of trypsin digests of bovine serum albumin modified with AFB(1) dialdehyde indicated selective modification of Lys455 and Lys548. Collectively, these results provide more insight into the mechanism of formation of AFB(1) dialdehyde-protein adducts and indicate that the formation of Lys adducts is a moderately efficient process. The binding of AFB(1) dialdehyde to albumin or the protonation of the N6-amino group retards the reaction with Lys residues.