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BACKGROUND: The clinical activity of allosteric inhibitors of mammalian target of rapamycin (mTOR) inhibitors in renal cell carcinoma (RCC) may be limited by upstream activation of phosphatidylinositol 3 (PI3)-kinase/Akt resulting from mTOR1 inhibition. On the basis of this rationale, 2 independent phase 2 trials (Perifosine 228 and 231) were conducted to assess the efficacy and safety of the novel Akt inhibitor perifosine in patients with advanced RCC who had failed on previous vascular endothelial growth factor (VEGF)-targeted therapy. METHODS: In the Perifosine 228 trial, 24 patients with advanced RCC received oral perifosine (100 mg daily). Perifosine 231 enrolled 2 groups that received daily oral perifosine (100 mg daily): Group A comprised 32 patients who had received no prior mTOR inhibitor, and Group B comprised 18 patients who had received 1 prior mTOR inhibitor. RESULTS: In the Perifosine 228 trial, 1 patient achieved a partial response (objective response rate, 4%; 95% confidence interval, 0.7%-20%), and 11 patients (46%) had stable disease as their best response. The median progression-free survival was 14.2 weeks (95% confidence interval, 7.7-21.6 weeks). In the Perifosine 231 trial, 5 patients achieved a partial response (objective response rate, 10%; 95% confidence interval, 4.5%-22.2%) and 16 patients (32%) had stable disease as their best response. The median progression-free survival was 14 weeks (95% confidence interval, 12.9, 20.7 weeks). Overall, perifosine was well tolerated, and there were very few grade 3 and 4 events. The most common toxicities included nausea, diarrhea, musculoskeletal pain, and fatigue. CONCLUSIONS: Although perifosine demonstrated activity in patients with advanced RCC after failure on VEGF-targeted therapy, its activity was not superior to currently available second-line agents. Nonetheless, perifosine may be worthy of further study in RCC in combination with other currently available therapies. Cancer 2012. © 2012 American Cancer Society.

BACKGROUND Brain metastases are a frequent complication in patients with metastatic clear cell renal cancer. Survival after whole-brain radiotherapy (WBRT) is disappointing. A retrospective analysis of multimodality treatment was performed in patients who had received linear accelerator (LINAC)-based stereotactic radiosurgery (SRS). METHODS Thirty-two patients underwent SRS-based treatment for 71 metastatic foci between 2000 and 2006. All patients had a Karnofsky performance status ≥70 and all 32 patients had extracranial metastatic disease (Radiation Therapy Oncology Group recursive partitioning analysis [RPA] Class 2). Survival was calculated from the time of diagnosis of brain metastases. The minimum potential follow-up was 1 year after SRS. Univariate and multivariate analysis of potential prognostic factors affecting survival was performed. RESULTS Twenty-six patients required only 1 SRS treatment (84%) to achieve central nervous system (CNS) control, whereas 5 patients received 2 to 3 treatments (16%). The median survival of renal cancer patients from the diagnosis of brain metastases was 10.1 months (95% confidence interval, 6.4-14.8 months). One-year and 3-year survival rates were 43% and 16%, respectively. The addition of surgery or WBRT did not appear to prolong survival. Immunotherapy after control of brain metastases with SRS appeared to result in significantly improved survival. Survival was also found to be strongly influenced by prognostic stratification of metastatic disease using Motzer or modified risk criteria. CONCLUSIONS The results of the current study demonstrated that SRS-based treatment of patients with up to 5 brain metastases from clear cell renal cancer is feasible and results in excellent CNS control. Survival beyond 3 years from the time of diagnosis of brain metastases was achievable in 16% of patients and was associated with the use of systemic immunotherapy with interleukin-2 and interferon but not antiangiogenic agents. Cancer 2008. © 2008 American Cancer Society.

BACKGROUND. Brain metastases are an alarming complication of advanced melanoma, frequently contributing to patient demise. The authors performed a retrospective analysis to determine whether the treatment of metastatic melanoma with biochemotherapy would result in similar outcomes if brain metastases were first controlled with aggressive, central nervous system (CNS)-directed treatment. METHODS. Seventy melanoma patients were treated with biochemotherapy for metastatic melanoma between 1999 and 2005. Of these, 20 patients had recently diagnosed brain metastases, whereas 50 did not. Brain metastases (if present) were treated with stereotactic radiosurgery ≥28 days prior to systemic therapy. All patients were treated with biochemotherapy consisting of either dacarbazine or temozolomide in combination with a 96-hour continuous intravenous infusion of interleukin-2 and subcutaneous interferon-α-2B. The primary endpoint was survival from the time of the initial diagnosis of metastatic disease. RESULTS. Median survival from the time of the diagnosis of metastatic melanoma was 15.8 months for patients with brain metastases and 11.1 months for those without CNS involvement (P = .26 by the log-rank test; P = .075 by the Gehan Wilcoxon test). Dacarbazine-based and temozolomide-based regimens appeared similar with regard to their effect on overall survival and CNS disease progression. A plateau in further brain recurrences was observed in patients who survived for > 20 months. CONCLUSIONS. Data from the current study suggest that the outcome of biochemotherapy is comparable in patients with and those without brain metastases, if brain metastases are controlled with multidisciplinary treatment. Prolonged survival can be achieved in approximately 15% of patients, regardless of whether or not brain metastases are present. Cancer 2007. © 2007 American Cancer Society.

C 2 F 4 was excited by using a 150 fs pulse in its longest-wavelength band to the Rydberg (3 s) state and then probed by photoionization techniques at 810 nm. The molecule relaxes in two consecutive steps (time constants 29 and 118 fs), probably via the ππ* state, which is lowered in energy by stretching and twisting the C=C bond. A coherent oscillation (350 fs) was found, which we assign to an overtone of the twist vibration (47.6 cm -1 ) in this state. We also conclude that dissociation to singlet and some triplet CF 2 only takes place in the hot ground state of C 2 F 4 from where also the C 2 F 4 triplet state is populated. The potentials and their conical intersections are discussed with respect to relaxation and dissociation, including also some new considerations of thermal processes.

BACKGROUND Single-agent chemotherapy with dacarbazine continues to be the standard of care for the treatment of metastatic melanoma. However, there is a large population of patients who have failed first-line therapy and might benefit from additional treatment. In the current study, the authors evaluated the antitumor effects and toxicity of vinorelbine therapy in patients who had failed one prior systemic therapy. METHODS Patients were required to have a histologic diagnosis of melanoma and be of Stage IV with measurable disease, a Southwest Oncology Group (SWOG) performance status (PS) of 0–2, no evidence of brain metastases, and adequate bone marrow and liver function. Treatment was comprised of vinorelbine given at a dose of 30 mg/m2/week by intravenous bolus. RESULTS Twenty-four patients were registered to the study, 3 of whom were determined to be ineligible. The 21 eligible patients had a median age of 58 years with a SWOG PS of 0 in 7 patients, 1 in 13 patients, and 2 in 1 patient. There were no complete or partial responses observed, for a response rate of 0 of the 21 patients studied (95% confidence interval [95% CI], 0–16%); the study closed after the first stage of accrual. The estimated median progression-free survival was 2 months (95% CI, 1.5–3.3 months) and the estimated median overall survival was 6 months (95% CI, 3.7–8.3 months). There was one death due to febrile neutropenia reported, with six patients experiencing one or more Grade 4 toxicities, including neutropenia/granulocytopenia, leukopenia, dyspnea, and fatigue. CONCLUSIONS Despite impressive preclinical activity against melanoma, vinorelbine does not appear to have enough clinical activity to be of interest in previously treated patients with disseminated melanoma. The progression-free and overall survival results noted in previously treated patients in the current study were similar to results reported in prior SWOG Phase II trials in untreated patients. The group of previously treated patients may be used to evaluate new agents for the treatment of disseminated melanoma. Cancer 2004. © 2004 American Cancer Society.

Potential energy surfaces for pericyclic reactions can easily be predicted by means of correlation diagrams. Whereas the initially excited state (called I B in this paper) may vary from molecule to molecule, its population is collected by a lower, dark state (2A) of always the same nature, which corresponds to a two-electron excitation. From there, the system leaves to the ground states of educt and product(s) via a conical intersection (Cl). Using transient absorption and transient ionization spectroscopy, we measured the lifetimes t 1B and t 2A of these states after initiating electrocyclic ring opening of 1,3-cyclohexadiene and some of its derivatives (α-terpinene, α-phellandrene and 7-dehydrocholesterol). t 2A can be considered the reaction time constant. Whereas t 2A = 5.2 ps for dehydrocholesterol, it is 80-100 fs for the other three molecules. We suggest that the former system needs some time to find the exit (the Cl) from the 2A surface, whereas in the latter cases the Cl is located right in the line of the steepest descent. We apply the same scheme to, and compile the time constants for, some other fast processes: the [1.3] sigmatropic reactions of norbornene and norbornadiene (t 2A = 220 and 210 fs) and the fast internal conversions of cycloheptatriene (80 fs) and several UV stabilizers. The latter two processes are suggested to take the same pathway as the pericyclic hydrogen shifts in these molecules. We also point out the similarity of the pericyclic potential surfaces to those of cis-trans isomerizations and give evidence that cis-stilbene (t 2A < 300 fs), too, is accelerated directly in the direction of the Cl. For cis-trans isomerization of longer polyenes there are however several 2A minima and conical intersections. We also give examples where additional branchings and competing reactions play a role.

What is the standard course of the cis-trans isomerization of nonpolar polyenes? Many results support a pathway in which only a central CH group rotates out of the plane, while the remaining parts of the molecule reorient within the plane ("hula-twist" mechanism). The intermediate structure through which the molecule passes corresponds to the geometry predicted for the conical intersection of the S1 and S0 potential energy surfaces (see picture).

The course of untreated mild hypothyroidism was followed in 67 nursing home residents (mean age 78 years). The diagnosis was based on a normal free thyroxine index (FTI) and elevated thyrotropin concentration (TSH 4.6 to 15.0 microIU/mL, nl less than or equal to 4.5 microIU/mL. FTI and FSH were measured in follow-up 42-378 (mean 161) days after the diagnosis of mild hypothyroidism had been made. In 45 patients initial TSH was less than 6.8 microIU/mL; in 23 of these subjects TSH returned to normal during the observation period, whereas in 22 TSH remained elevated. In all 22 residents whose initial TSH was greater than 6.8 microIU/mL, TSH remained elevated at follow-up. In 4 subjects whose initial TSH concentrations ranged from 5.0 to 9.6 microIU/mL, FTI fell below normal 91-141 days after the diagnosis of mild hypothyroidism was made. Clinical progression of the signs or symptoms of hypothyroidism was not detected in the 4 patients who developed hypothyroxinemia. Three demonstrated positive thyroid antibody titers, and 1 had myasthenia gravis. These observations suggest a need for replacement therapy in debilitated patients with mild hypothyroidism and evidence of thyroid autoimmunity.

The authors performed a retrospective analysis of 87 consecutive immunocompromised patients who underwent open-lung biopsy at the University of Utah Medical Center, Salt Lake City, Utah, from January 1971 to June 1982. A specific histologic diagnosis was obtained in 62 (71%) of the patients, 33 of whom had infections. Pneumocystis carinii was the most common microbial pathogen (16 patients), but no cases have been observed since 1980 when the routine use of prophylactic trimethoprim/sulfa began. The other specific diagnoses included malignancy or drug-induced lung disease. Specific therapy was available for 52 patients, and in 33 cases, a change in therapy was necessary to treat according to the lung biopsy diagnosis. Forty-one patients received an adequate course of therapy and 27 (66%) of these improved clinically, including 16 of 26 patients with infections, 11 of 14 with malignancies, and 1 of 2 with a vasculitis. Among the subgroup of 33 patients for whom a new, specific therapeutic option was available as a result of the biopsy diagnosis 21 (64%) responded to the treatment. Eleven significant operative complications were encountered, but no deaths were attributable to the biopsy. An open-lung biopsy in immunocompromised patients is a relatively safe, accurate diagnostic procedure which frequently facilitates appropriate therapy and clinical improvement.

SF6 was dissociated by a focussed cw CO2 laser at the 10P20 and 10P32 lines. Isotope selectivity > 10 was observed at 0.25 to 0.5 mbar. Collisions play no role in the focus, whose radius is smaller than the mean free path length. But most of the reaction occurs in the conical region of the beam, with radius up to 1 mm. Although collisions are not negligible in this part of the beam, they are not sufficient to destroy selectivity. — Both isotopes diffuse into the beam only after preheating to more than 1000 K. So, obviously, selective excitation is possible at such a high temperature. — Analytical formulas were derived for the radial (r) distribution of temperature T and its dependence on laser power P, molecule density n and absorption cross section σ. Because of the temperature dependence of σ and n and of the heat conductivity, T depends only on the 7th root of σnPlnr. This temperature distribution was used for a numerical calculation of the conversion rate, which was then compared with the experimental yields. The observed conversion can only be explained, if the vibrational temperature is about 110 K higher than the translational. — The observed quantum yield is much smaller than for pulsed excitation. But optimization by means of our formulas shows that it could be raised by orders of magnitude, so that application for practical isotope separation is conceivable.