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Fil: Orte, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones Científicas y Técnicas para la Defensa. Unidad de Investigación y Desarrollo Estratégicos para la Defensa. Centro de Investigaciones en Láseres y Aplicaciones; Argentina Fil: Wolfram, E. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Wolfram, E. Servicio Meteorológico Nacional; Argentina Fil: Wolfram, E. Universidad Tecnológica Nacional. Facultad Regional Buenos Aires; Argentina Fil: Luccini, Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Excelencia en Productos y Procesos de Córdoba; Argentina Fil: Luccini, Eduardo. Ponti cia Universidad Católica Argentina. Facultad de Química e Ingeniería del Rosario; Argentina Fil: D'Elia, R. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Lusi, Anabela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Orte, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Lusi, Anabela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones Científicas y Técnicas para la Defensa. Unidad de Investigación y Desarrollo Estratégicos para la Defensa. Centro de Investigaciones en Láseres y Aplicaciones; Argentina Fil: Pallotta, J. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones Científicas y Técnicas para la Defensa. Unidad de Investigación y Desarrollo Estratégicos para la Defensa. Centro de Investigaciones en Láseres y Aplicaciones; Argentina Fil: Nollas, Fernando. Servicio Meteorológico Nacional; Argentina Fil: Carmona, Facundo. Universidad Nacional del Centro de la Provincia de Buenos Aires. Instituto de Hidrología de Llanuras; Argentina Fil: Carmona, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Papandrea, Sebastián. Servicio Meteorológico Nacional; Argentina Fil: Cabezas, Marcelo D. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones Científicas y Técnicas para la Defensa. Unidad de Investigación y Desarrollo Estratégicos para la Defensa. Centro de Investigaciones en Láseres y Aplicaciones; Argentina Fil: Carbajal Benítez, Gerardo. Servicio Meteorológico Nacional; Argentina Fil: Mizuno, Akira. Universidad de Nagoya. Instituto de Investigación Ambiental Espacio-Tierra; Japón Resumen: El monitoreo simultáneo de la radiación solar localizada en diferentes rangos espectrales de banda ancha tiene varias ventajas importantes sobre el monitoreo aislado, tanto para la investigación básica como aplicada. Su integración en una red bajo protocolos estandarizados tiene a su vez valiosos beneficios, incluida la posibilidad de caracterizar geográficamente los niveles de radiación solar en grandes regiones. Recientemente, se ha desplegado en Argentina una red integrada de monitoreo de irradiancia solar UV-Total en 8 estaciones con nuevos instrumentos, sitios de medición y protocolos en el marco del proyecto Saver-Net (Japón, Argentina y Chile) llevado a cabo durante el período 2013- 2018. La red es administrada por el Servicio Meteorológico Nacional (SMN) de Argentina y el Instituto de Investigaciones Científicas y Técnicas para la Defensa (CITEDEF- UNIDEF). En este trabajo se describe la estructura y capacidad de la red y varios logros iniciales de la red argentina de monitoreo de irradiancia solar UV-Total con el objetivo de dar a conocer a la comunidad científica y poner a disposición estas bases de datos para su amplio uso en la investigación básica y aplicada. Además, se presenta la caracterización de los sitios donde se encuentra cada nodo de monitoreo de la red. Se observan valores extremos por encima de 1000 Wm−2 para la irradiancia solar Total, 60 Wm−2 para la irradiancia solar UVA e índices UV por encima de 9, aún en los sitios ubicados de la red Saver-Net ubicados más al sur, con su consecuente significancia en aplicaciones prácticas como la generación de energía solar e implicancias en la salud de las personas como el riesgo de contracción de eritema. Abstract: Simultaneous localized solar radiation monitoring in different broadband spectral ranges has several important advantages over isolated measurements for both basic and applied research. Its integration into a network under standardized protocols has, in turn, worthy benefits including the possibility to characterize geographically the solar radiation levels in large regions. Recently, an integrated UV-Total solar irradiance monitoring network has been deployed in Argentina in 8 stations with new instruments, measurement sites, and protocols into the frame of the Saver-Net project (Japan, Argentina, and Chile) carried out during the period 2013-2018. The network is managed by the Argentine Servicio Meteorol´ogico Nacional (SMN) and Instituto de Investigaciones Cient´ıficas y T´ecnicas para la Defensa (CITEDEFUNIDEF). In this paper, the structure, capability and several initial achievements of the Argentine UV-Total solar irradiance monitoring network are described with the aim to make these databases available to the scientific community for their broad use in basic and applied research. In addition, the irradiance characterization at each monitoring node of the network is presented. Extreme values over 1000 Wm−2 of Total solar irradiance, 60 Wm−2 of UVA solar irradiance and UV Index of 9 are registered even in the southernmost stations, with their consequent signification for the practical applications of the solar energy and health implications such as the risk to cause erythema.

Background Locally advanced basal cell cancer is a rare and challenging clinical problem. Historically, these patients were treated with aggressive surgery or radiotherapy. Most sporadic basal cell carcinomas have somatic mutations in the hedgehog pathway. Oral hedgehog inhibitors induce rapid and often complete clinical responses in locally advanced basal cell tumors. Unfortunately, these responses are usually transient. We hypothesized that treatment failure represents persistence of drug resistant cells that could be eradicated by addition of localized radiotherapy. Materials and Methods We performed a retrospective review of our patients with locally advanced basal cell cancer treated with sonidegib or vismodegib induction therapy who were treated with added superficial radiotherapy at the time of maximal response. Results Twelve patients met inclusion criteria. All patients achieved a complete response following hedgehog inhibitor therapy with addition of radiotherapy. Progression-free survival at 40 months was 89%, with a median follow-up of 40 months. Relapses occurred in only 2 of 12 patients (16.6%). Nine patients experienced grade I–II toxicity from hedgehog inhibitor induction therapy (taste changes [3], weight loss [3], muscle cramps [3]). Eight patients experienced mild radiotherapy-induced skin toxicity during concurrent therapy. No patients had to discontinue treatment. Conclusion Induction therapy with hedgehog inhibitors followed by addition of concurrent radiation therapy resulted in an extremely high clinical response rate with relatively minor and reversible toxicity. This gave a high rate of progression-free survival and a low disease-specific progression rate. Further prospective evaluation of this treatment approach is needed to confirm the apparent clinical activity. Implications for Practice Locally advanced basal cell cancers are challenging to treat. Previously, aggressive surgical resection or radiotherapy represented the best treatment options. Most basal cell cancers have somatic mutations in the hedgehog pathway. Oral inhibitors of this pathway produce rapid but transient clinical responses. This study reports 12 patients treated with hedgehog inhibitor induction therapy to near-maximal response. Addition of concurrent involved field radiotherapy resulted in a very high complete response rate with minimal toxicity. There was prolonged progression-free survival in 90% of patients. This study identified a novel treatment approach for patients with advanced basal cell carcinoma.

Background Nivolumab is approved in the US and EU for the adjuvant treatment of resected stage III-IV melanoma based on results from the CheckMate-238 clinical trial.1,2 However, the trial did not enroll any patients with Stage IIIA disease per the American Joint Committee on Cancer (AJCC) 7th edition criteria and included a limited number of patients with stage IIIA disease per the AJCC 8th edition.3,4,5Recognizing the need for real-world data to assess outcomes of patients with resected stage IIIA melanoma treated with adjuvant nivolumab, a non-interventional study was conducted to investigate treatment patterns and outcomes among patients receiving adjuvant nivolumab within the US community practice setting. Methods A retrospective analysis of the US Oncology Network’s iKnowMed medical data was conducted to examine patients with resected stage IIIA melanoma treated with adjuvant nivolumab between 01-Jan-2018 and 31-Dec-2019 with a follow-up period through 31-Mar-2020. Patients were followed for up to 27 months after their sentinel lymph node biopsy. Baseline demographic/clinical characteristics and treatment patterns were examined descriptively. Duration of treatment (DOT) and overall survival were analyzed using the Kaplan-Meier method. Results A total of 58 patients with stage IIIA melanoma treated with adjuvant nivolumab were identified. Median age was 57.8 years (range 21.5–93.5), 62.1% were male, and 75.9% were Caucasian. Among patients with a documented Eastern Cooperative Oncology Group (ECOG) performance status (51.7%), all had an ECOG score of 0 or 1. Median follow-up time was 12.6 months (range 0.3–25.1). Median DOT was 10.6 months (range 6.8–12.0). Overall survival rates at 12 and 24 months were 97.7% (95% CI 84.6–99.7) and 92.2% (95% CI 69.6–98.2), respectively. Conclusions This real-world analysis of patients with stage IIIA melanoma treated with adjuvant nivolumab showed that a large proportion of patients were alive at the end of the study period, suggesting these patients have a favorable prognosis. Further investigation and follow-up is warranted to assess clinically relevant outcomes among patients with resected stage IIIA melanoma. Ethics Approval The study was approved by US Oncology Inc’s Institutional Review Board, approval number 20-020E-2020-0224-01. References Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. NEJM 2017;377:1824–35. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: A randomized, double-blind, phase 3 trial (CheckMate 238). Ann Oncol 2017;28(5):632–33. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27(36):6199–6206. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 2017;67(6):472–492. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Cutaneous Melanoma Version 3.2020 - May 18, 2020. 2020.

This study investigated the relationship between listening comprehension and reading comprehension to determine if environmental factors might be contributing to a possible change in the equalization age for these two comprehension modalities from what was theorized by Thomas Sticht. The study employed a counterbalanced design to measure the listening and reading comprehension of 223 fourth, 347 sixth, and 368 eighth grade students. The authors administered the Reading Comprehension sub-test of the Gates-MacGinitie Reading Test Fourth Edition to measure both reading and listening comprehension. Mean reading scores significantly exceeded mean listening scores at grades 4, 6, and 8. In addition, the results indicate a significant relationship between listening comprehension and proficient reading. The potential influence of environmental factors on the reading/listening relationship is discussed.

Introduction Le nivolumab est approuve dans le traitement adjuvant du melanome ; une posologie fixe de 480 mg toutes les 4 semaines (Q4W) en monotherapie a ete approuvee aux Etats-Unis et en Europe (mars 2018 et octobre 2019 respectivement). Nous avons analyse les resultats en vie reelle de differents schemas posologiques de nivolumab en adjuvant dans le cadre de pratique clinique en oncologie dans les centres dit « community centers » aux Etats-Unis, faisant reference aux centres prives. Materiel et methodes Nous avons effectue un examen retrospectif des dossiers electroniques de patients du reseau d’oncologie americain iKnowMed™ pour des patients atteints de melanome et ayant recu du nivolumab entre le 1er mars 2018 et le 28 fevrier 2019. Les patients ont ete regroupes par schemas posologiques de nivolumab : cohorte 1 (C1), nivolumab 480 mg Q4W de novo (aucun traitement anterieur par nivolumab) ; cohorte 2 (C2), passage au nivolumab 480 mg Q4W apres avoir recu du nivolumab 240 mg ou 3 mg/kg toutes les 2 semaines (Q2W) ; cohorte 3 (C3), nivolumab 3 mg/kg Q2W de novo ; cohorte 4 (C4), nivolumab 240 mg Q2W de novo. Les patients ont ete suivis pendant ≥ 6 mois apres le debut du nivolumab. Les schemas de traitement et les donnees de tolerance ont ete compares entre les cohortes. L’appariement des scores de propension a ete effectue pour minimiser le biais de selection potentiel (C1 : C4 et C2 : C4). Resultats Au total, 191 patients atteints de melanome ont ete identifies (C1, n = 40 ; C2, n = 74 ; C3, n = 22 ; C4, n = 55). Les caracteristiques demographiques et cliniques a l’initiation du traitement etaient similaires entre les 4 cohortes ; cependant les patients C3 avaient un indice de masse corporelle moyen le plus bas (25,8 kg/m2) et la plus faible proportion de patients avec un statut de performance ECOG (Eastern Cooperative Oncology Group) de 0 (32 %). La duree du traitement et l’incidence des evenements indesirables lies au traitement (EILT) et des EILT severes etaient similaires entre toutes les cohortes non ajustees. Ces resultats ont ete etayes par des analyses de cohorte appariees (C1 : C4 et C2 : C4). Les taux de completion du traitement (duree de 12 mois) ou de traitement en cours et les raisons de l’arret etaient variables par cohorte. Discussion Cette analyse des donnees en vie reelle des schemas posologiques de nivolumab montre que la duree du traitement et les EI sont similaires entre les schemas posologiques Q2W et Q4W chez les patients atteints de melanome.

Introduction: Nivolumab is approved for the adjuvant treatment of melanoma, and a 480 mg every 4 weeks (Q4W) flat-dosing monotherapy regimen was approved in the United States (March 2018). We examined real-world outcomes with different adjuvant nivolumab dosing regimens in a US community oncology setting. Methods: We conducted a retrospective chart review of US Oncology Network iKnowMed™ electronic health records of patients with melanoma receiving nivolumab from March 1, 2018, to February 28, 2019. Patients were grouped by nivolumab regimen: cohort 1 (C1), nivolumab 480 mg Q4W de novo (no prior nivolumab treatment); cohort 2 (C2), switched to nivolumab 480 mg Q4W after receiving nivolumab 240 mg or 3 mg/kg every 2 weeks (Q2W); cohort 3 (C3), nivolumab 3 mg/kg Q2W de novo; or cohort 4 (C4), nivolumab 240 mg Q2W de novo. Patients were followed for ≥6 months after nivolumab initiation. Treatment patterns and safety outcomes were compared between cohorts. Propensity score matching was performed to minimize potential selection bias (C1:C4 and C2:C4). Results: A total of 191 patients with melanoma were identified (C1, n=40; C2, n=74; C3, n=22; C4, n=55). Baseline demographic and clinical characteristics were similar in all 4 cohorts, however, C3 patients had the lowest mean body mass index (25.8 kg/m2) and the lowest proportion of patients with Eastern Cooperative Oncology Group performance status of 0 (32%). Duration of treatment and incidence of treatment-related adverse events (TRAEs) and severe TRAEs were similar across all unadjusted cohorts (Table). These results were supported by matched cohort analyses (C1:C4 and C2:C4). Rates of treatment completion (12-month course) or ongoing treatment and reasons for discontinuation varied by cohort (Table). TableCohort 1Cohort 2Cohort 3Cohort 4Outcomes: unadjusted study populationNIVO 480 mg Q4W (de novo) N=40NIVO 480 mg Q4W (switched) N=74NIVO 3 mg/kg Q2W (de novo) N=22NIVO 240 mg Q2W (de novo) N=55Median DoT, months (95% CI)aNR (5.3-NE)9.5 (7.5-11.1)8.3 (5.2-11.7)10.8 (10.6-NE)Completed planned 12-month treatment or treatment is ongoing, %73735971Most common reasons for treatment discontinuation, %Progression1031418Toxicityb131196Patient preference0592Physician preference0400Severe TRAE, %c,d1081811Any TRAE, %d55575556Fatigue33242331Rash15181813Diarrhea1016913Hypothyroidism155511Pruritus5854Nausea5456aDoT was defined as the interval between the date of initiation of nivolumab and the last administration date, including treatment holidays or other breaks no more than 180 consecutive days in length; P=0.5797 (calculated from a test analogous to McNemar's test for correlated binary proportions [Klein and Moeschberger,1997]).bToxicity resulting in discontinuation may or may not be an AE that was explicitly attributed to NIVO.cAEs explicitly attributed to NIVO dosing regimen that led to dose withheld, dose modification, dose permanently discontinued, hospitalization, or emergency department visit. AE severity was based in part on the CTCAE v.5.0 grading system, and dose modifications were recommended in cases of adverse reactions listed in the package insert.dOccurring within 6 months from treatment initiation.AE, adverse event; CI, confidence interval; DoT, duration of treatment; NE, not estimable; NIVO, nivolumab; NR, not reached. Conclusions: This real-world data analysis of nivolumab dosing regimens shows that duration of therapy and AEs are similar between the Q2W and Q4W regimens in patients with melanoma. Citation Format: Wolfram Samlowski, Nicholas J. Robert, Esmond D. Nwokeji, Bismark Baidoo, Brad Schenkel, Andriy Moshyk, Srividya Kotapati, Tayla Poretta, Jeffrey S. Weber. Real-world outcomes in patients receiving nivolumab 480 mg every 4 weeks vs other dosing regimens as treatment for melanoma in the adjuvant setting [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1043.

Atypical fibroxanthomas (AFX) are rare skin tumors. These generally are superficial tumors, usually 376 colonies. The patient could not tolerate additional chemotherapy. She was therefore treated with the oral targeted agent pazopanib. The patient developed a dramatic biopsy-confirmed complete response. After 11 months of pazopanib treatment, a repeat CTC-derived culture sample grew only 8 colonies/10 ml blood. The complete response to pazopanib is still ongoing at over 41 months. To our knowledge, this is the first demonstration of clinical complete response of a PDS tumor following targeted therapy. An additional novel feature was the demonstration that CTC-derived colonies could be grown from the blood of a PDS patient. The number of colonies appeared to correlate with the clinical treatment response and seemed to function as a potential prognostic marker.

The main primary photoproducts of cycloocta-1,3,5-triene (COT) are a strained mono-E isomer, Z,Z-octatetraene (OT, from electrocyclic ring opening) and benzene + ethylene. We investigated the excited-state dynamics of COT by time-resolved mass spectroscopy, probing by near-IR photoionization. Unexpectedly, we found only one reaction channel. We assign it to the pericyclic reactions. Evidence for an early branching between this and the Z–E channel is taken from previous resonance Raman data. This channel confirms previously formulated rules on the excited states involved, the reaction path and driving forces and contributes to their rationalization. Bicyclo[4.2.0]octa-2,4-diene undergoes only two pericyclic reactions: ring opening to OT and cleavage to benzene + ethylene. We investigated it briefly in its equilibrium mixture with COT. The data are consistent with a common path on the excited surfaces. Suggestions are made for structures of conical intersections, and driving forces are considered. All processes were found to be barrierless.

Open Access Journal, Hypericum calycinum L. (section Ascyreia) is a species of the Hypericum genus, relative to the medicinal plant H. perforatum (St. Jonn’s worth). Unlike the widely studied H. perforatum, it is characterized by the lack of hypericins production. However, research has revealed its commensurable antidepressant activity, as compared with the latter species, and shown the presence of polyphenolics with marked radical scavenging activity. In order to develop an in vitro system with the potential of a novel source of bioactive constituent’s characteristic for the Hypericum genus, we initiated in vitro cultures of H. calycinum. In the present work we studiy the effect of exogenous BA and IBA treatments on the developmental patterns, enzymatic and non-enzymatic antioxidant defence of hypericin non-producing Hypericum calycinum shoot cultures. It was shown that supplementation of PGR led to stimulation of phenylalanine ammonia-lyase and superoxide dismuthase, as well as non-enzymatic antioxidant glutathione. However, they inhibited glutathione reductase, as well as lowered the levels of fl avonoids, ascorbate and dehydroascorbate in comparison with plant growth regulators-free control. Further on, it was established that elevation of IBA concentration slightly stimulated axillary shoot formation and shoot length, but inhibited polyphenolic levels in vitro. These results are in agreement with our previous results of interrelations between biomass formation and polyphenolics production in other Hypericum species in vitro. An in vitro culture system optimization is in progress in order to increase biomass production and retain biosynthetic capacity of the species.

Circulating tumor cells (CTC) are rarely detected in the blood of cancer patients, even though they are a direct harbinger of eventual patient demise. We developed an innovative CTC culture technology to allow more sensitive isolation, expansion, and characterization of viable colonies from patient blood. In this assay, the entire leukocyte fraction from 10 ml of anticoagulated patient blood is placed into culture medium without any pre-selection. After 16 days in culture, CTC derived colonies are counted. As a proof-of-principle, blood samples from 58 Stage IIa-IV melanoma patients were tested. Ninety percent of these samples grew colonies. The colony numbers ranged from 0 - 308 (mean 63 ± 9.5 SEM). Ten normal volunteers had virtually no growth (mean 0.5 ± 1.4 colonies). Colonies were harvested using a micropipette for characterization. Tumor-cell containing spheroids were embedded in paraffin, sectioned, and stained with melanoma-specific mAb for histologic characterization. MITF proved to be the most consistent immunostain that identified melanoma cells in these colonies. A host-cell component in colonies was also identified using CD68 and CD43 mAb staining. Following enzymatic dissociation of colonies, a variety of immunostains were tested. Papanicolau staining proved most useful for identifying the abnormal nuclei of tumor cells. Flow cytometry could readily distinguish host and tumor cell populations based on DNA content and forward/side scatter in dissociated colonies. The stem cell marker ALDH1A1 associated with the aneuploid population, but CD45 was expressed on both diploid and aneuploid cells. The ability to repeatedly isolate CTC derived colonies from cancer patient blood samples opens the door to a novel type of long-term clinical monitoring. This novel CTC culture technology may prove useful to perform molecular characterization, assessment of treatment response, and testing of drug sensitivity and resistance in patients during treatment.

Metastatic Merkel Cell carcinoma (MCC) is a highly unusual and aggressive skin cancer that presents as a small, pink to violet skin lesion and metastasizes early in its growth. Metastatic MCC is generally treated with small cell lung cancer chemotherapy regimens, because the tumor consists of neuroendocrine cells, but patients generally do not have durable responses. The pathogenesis of MCC has recently been attributed to the Merkel Cell polyoma virus. This virus activates the cellular retinoblastoma oncoprotein and cell cycle machinery, triggering continual cellular proliferation. A 77-year-old man developed extensive MCC metastases, involving more than one fourth of his scalp and numerous cervical lymph nodes. Following failure of initial chemotherapy and radiation, effective palliation was achieved by using a sequence of electron-beam radiotherapy, low dose gemcitabine, and etoposide, resulting in significant periods of tumor regression and prolonged survival. A novel circulating tumor cell (CTC) culture assay was performed on four separate clinic visits during the treatment period. Tumor colonies were cultured from the patient’s peripheral blood and CTC colony counts were correlated with clinical treatment response. Not only did the patient respond to palliative cell cycle directed chemotherapy and electron beam radiation, but we demonstrated that CTC can be cultured from peripheral blood of MCC patients and serve as a predictive marker to monitor treatment response.

Conditional survival (CS) is a clinically useful prediction measure which adjusts a patient’s prognosis based on their duration of survival since initiation of therapy. CS has been described in numerous malignancies, and recently described in patients with metastatic renal cell carcinoma (mRCC) who received vascular endothelial growth factor tyrosine kinase inhibitor (VEGFTKI) therapy. However, CS has been not reported in the context of mRCC treated with high-dose interleukin-2 therapy (HDIL-2). A total of 176 patients with histologically confirmed metastatic clear cell RCC (mccRCC) treated with HDIL-2 at the University of Utah Huntsman Cancer Institute from 1988–2012 were evaluated. Using the Heng/IMDC model, they were stratified by performance status and prognostic risk groups. Two-year CS was defined as the probability of surviving an additional two years from initiation of HDIL-2 to 18 months after the start of HDIL-2 at three-month intervals. The median overall survival (OS) was 19.9 months. Stratifying patients into favourable (n = 35; 20%), intermediate (n = 110; 63%), and poor (n = 31; 18%) prognostic groups resulted in median OS of 47.5 (HR 0.57, 95% CI 0.35–0.88, p = 0.0106 versus intermediate), 19.6 (HR 0.33, 95% CI 0.10–0.33, p < 0.0001 versus poor), and 8.8 (HR 5.34, 95% CI 3.00–9.62, p < 0.0001 versus favourable) months respectively. Two-year overall CS increased from 43% at therapy initiation to 100% at 18 months. These results have significant ramifications in prognostication. Furthermore, it is important when counseling patients with mccRCC who have completed treatment with HDIL-2 and are in active follow-up.

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.

Merkel cell carcinoma (MCC) is a highly aggressive skin malignancy. The growing incidence and recognition of this cancer in elderly or immunosuppressed individuals suggests that it is becoming an increasing clinical challenge. MCC recently has been demonstrated to have a probable viral pathogenesis related to a novel member of the polyomavirus (termed Merkel cell polyomavirus [MCV]). The molecular pathogenesis of viral carcinogenesis is currently being worked out in MCC. Current diagnostic and therapeutic strategies are discussed, with an eye toward the future development of molecularly targeted treatments.

A MESSAGE FROM ASCO'S PRESIDENT It has been forty years since President Richard Nixon signed the National Cancer Act of 1971, which many view as the nation's declaration of the “War on Cancer.” The bill has led to major investments in cancer research and significant increases in cancer survival. Today, two-thirds of patients survive at least five years after being diagnosed with cancer compared with just half of all diagnosed patients surviving five years after diagnosis in 1975. The research advances detailed in this year's Clinical Cancer Advances demonstrate that improvements in cancer screening, treatment, and prevention save and improve lives. But although much progress has been made, cancer remains one of the world's most serious health problems. In the United States, the disease is expected to become the nation's leading cause of death in the years ahead as our population ages. I believe we can accelerate the pace of progress, provided that everyone involved in cancer care works together to achieve this goal. It is this viewpoint that has shaped the theme for my presidential term: Collaborating to Conquer Cancer. In practice, this means that physicians and researchers must learn from every patient's experience, ensure greater collaboration between members of a patient's medical team, and involve more patients in the search for cures through clinical trials. Cancer advocates, insurers, and government agencies also have important roles to play. Today, we have an incredible opportunity to improve the quality of cancer care by drawing lessons from the real-world experiences of patients. The American Society of Clinical Oncology (ASCO) is taking the lead in this area, in part through innovative use of health information technology. In addition to our existing quality initiatives, ASCO is working with partners to develop a comprehensive rapid-learning system for cancer care. When complete, this system will provide physicians with personalized, real-time information that can inform the care of every patient with cancer as well as connect patients with their entire medical teams. The rapid learning system will form a continuous cycle of learning: securely capturing data from every patient at the point of care, drawing on evidence-based guidelines, and evaluating quality of care against those standards and the outcomes of other patients. Clinical trials are another area in which collaboration is critical. Increasing clinical trial participation will require commitment across the cancer community from physicians, patients, insurers, hospitals, and industry. A 2010 report by the Institute of Medicine described challenges to participation in trials by both physicians and patients and provided recommendations for revitalizing clinical trials conducted through the National Cancer Institute's Cooperative Group Program. ASCO has pledged its support for the full implementation of these recommendations. More broadly, ASCO recently outlined a bold vision for translational and clinical cancer research for the next decade and made recommendations to achieve that vision. Accelerating Progress Against Cancer: ASCO's Blueprint for Transforming Clinical and Translational Research, released in November, calls for a research system that takes full advantage of today's scientific and technologic opportunities and sets a high-level agenda for policy makers, regulators, and advocates. Cancer research has transformed cancer care in the past forty years, and this year's Clinical Cancer Advances illustrates how far we have come in the past year alone. We now have a tremendous opportunity to use today's knowledge and collaborate across all facets of cancer care to conquer this deadly disease. Michael P. Link, MD President American Society of Clinical Oncology

Objective We reviewed the imaging studies of patients with known metastatic renal cell carcinoma (RCC) in order to more accurately assess where retroperitoneal lymphadenopathy occurs. Methods The database of patients with metastatic RCC was reviewed and 101 patients were found from 2002 to 2006. Each patient's CT scans were then reviewed. Twenty-seven retroperitoneal sections were defined for each patient, with 3 positions in each of the x-, y-, and z-axis. Lymph nodes greater than 1 cm were then counted for each section. Results Of the 101 patients, 31, of whom 28 qualified, were found to have retroperitoneal lymphadenopathy of a least 1 cm or greater. Two-thirds of nodes (87 out of 124) exhibited a suprahilar, intra-aortocaval, and retro-aortocaval trend of lymph node enlargement. Three patients (11%) had isolated infrahilar nodes, while 8 patients (29%) exhibited a skip lesion pattern by imaging criteria. Only 4 patients (14%) were noted to have lymph nodes that were confined to the ipsilateral (paraaortic or paracaval) nodes in the perihilar and infrahilar region, which would be readily accessible during renal surgery. Conclusions Lymphatic drainage in RCC is ill-defined, likely due to multiple lymphatic outflow channels. However, after a review of retroperitoneal lymphadenopathy imaging in patients with known metastatic RCC, there does seem to be a cephalad, posterior, and medial drainage pattern.

5-Aza-2'-deoxycytidine (decitabine) is a drug targeting the epigenetic abnormalities of tumors. The basis for its limited efficacy in solid tumors is unresolved, but may relate to their indolent growth, their p53 genotype or both. We report that the primary molecular mechanism of decitabine-depletion of DNA methyltransferase-1 following its "suicide" inactivation-is not absolutely associated with cell cycle progression in HCT 116 colon cancer cells, but is associated with their p53 genotype. Control experiments affirmed that the secondary molecular effects of decitabine on global and promoter-specific CpG methylation and MAGE-A1 mRNA expression were S-phase dependent, as expected. Secondary changes in CpG methylation occurred only in growing cells ~24-48 h after decitabine treatment; these epigenetic changes coincided with p53 accumulation, an index of DNA damage. Conversely, primary depletion of DNA methyltransferase-1 began immediately after a single exposure to 300 nM decitabine and it progressed to completion within ~8 h, even in confluent cells arrested in G 1 and G 2/M. Our results suggest that DNA repair and remodeling activity in arrested, confluent cells may be sufficient to support the primary molecular action of decitabine, while its secondary, epigenetic effects require cell cycle progression through S-phase.

Purpose: Metastatic melanoma patients have a poor prognosis. No chemotherapy regimen has improved overall survival. More effective treatments are needed. Docetaxel has clinical activity in melanoma and may be more active when combined with vinorelbine. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown activity as an adjuvant melanoma therapy. We carried out a phase II study of these agents in patients with stage IV melanoma. Methods: Patients had documented stage IV melanoma and may have had prior immuno or chemotherapy. Previously treated brain metastases were allowed. Docetaxel (40 mg/m2IV) and vinorelbine (30 mg/m2IV) were administered every 14 days, followed by GM-CSF (250 mg/m2 SC on days 2 to 12). The primary endpoint of the study was 1-year overall survival (OS). Secondary objectives were median overall survival, response rate (per RECIST criteria), and the toxicity profiles. Results: Fifty-two patients were enrolled; 80% had stage M1c disease. Brain metastases were present in 21%. Fifty-two percent of patients had received prior chemotherapy, including 35% who received prior biochemotherapy. Toxicity was manageable. Grade III/IV toxicities included neutropenia (31%), anemia (14%), febrile neutropenia (11.5%), and thrombocytopenia (9%). DVS chemotherapy demonstrated clinical activity, with a partial response in 15%, and disease stabilization in 37%. Six-month PFS was 37%. Median OS was 11.4 months and 1-year OS rate was 48.1%. Conclusions: The DVS regimen was active in patients with advanced, previously treated melanoma, with manageable toxicity. The favorable 1-year overall survival and median survival rates suggest that further evaluation of the DVS regimen is warranted. © 2011 The Author(s).

Objective: Ipilimumab is a fully human, anti–cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody that has demonstrated antitumor activity in advanced melanoma. We evaluated the safety and efficacy of ipilimumab alone and in combination with dacarbazine (DTIC) in patients with unresectable, metastatic melanoma. Methods: Chemotherapy-naive patients were randomized in this multicenter, phase II study to receive ipilimumab at 3 mg/kg every 4 weeks for four doses either alone or with up to six 5-day courses of DTIC at 250 mg/m2/day. The primary efficacy endpoint was objective response rate. Results: Seventy-two patients were treated per-protocol (ipilimumab plus DTIC, n = 35; ipilimumab, n = 37). The objective response rate was 14.3% (95% CI, 4.8–30.3) with ipilimumab plus DTIC and was 5.4% (95% CI, 0.7–18.2) with ipilimumab alone. At a median follow-up of 20.9 and 16.4 months for ipilimumab plus DTIC (n = 32) and ipilimumab alone (n = 32), respectively, median overall survival was 14.3 months (95% CI, 10.2–18.8) and 11.4 months (95% CI, 6.1–15.6); 12-month, 24-month, and 36-month survival rates were 62%, 24% and 20% for the ipilimumab plus DTIC group and were 45%, 21% and 9% for the ipilimumab alone group, respectively. Immune-related adverse events were, in general, medically manageable and occurred in 65.7% of patients in the combination group versus 53.8% in the monotherapy group, with 17.1% and 7.7% ≥grade 3, respectively. Conclusion: Ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients, and the results support further investigations of ipilimumab in combination with DTIC.

Melanoma continues to be a major health problem with no effective therapy. Melanocytes, both benign and malignant, express many anti-apoptotic factors. Survivin is a member of the family of inhibitors of apoptosis proteins (IAP) and is preferentially expressed in tumor cells, including melanoma. YM155 is a small molecule suppressant of survivin that has been shown in preclinical cell lines, xenograft models and phase I studies to have anti-tumor activity. Methods: This was an open-label, multi-center, study of YM155 monotherapy in subjects with unresectable stage III or IV melanoma. Thirty-four chemotherapy naive subjects were treated with YM155 at a dose of 4.8 mg/m2/day administered by continuous infusion for 168-hours (7 days) followed by a 14-day rest period, for up to 6 cycles or until disease progression. Results: One subject had a partial response to treatment seen at cycle two and lasting through cycle eight. Median progression-free survival was 1.3 months (95% CI; 1.3–2.7). Median overall survival was 9.9 months (95% CI; 7.0–14.5). Overall, YM155 was well tolerated with the most common (>20%) adverse events reported as fatigue, nausea, pyrexia, headache, arthralgia and back pain. Only four subjects required dose reductions. Conclusions: YM155 was well tolerated in subjects with advanced melanoma; however, the pre-specified primary end-point for efficacy which required two responders in 29 evaluable subjects was not achieved.

Probing the first excited-state of H 2 O, HDO and D 2 O by ionization at 810 nm reveals in the parent-ion yields time constants of 1.8, 2.1 and 2.5 fs, respectively, during which the molecule leaves the Franck–Condon region, stretching the bonds of by about 0.25 A. The OH + signal rises slightly more slowly (1.8 + 1.7 fs), because only then is the dissociation energy of the parent ion overcome. The subsequent decay (3.3 fs) is caused by the decreasing ionization probability. The detection of such short times is intimately connected with the sensitivity of the probe technique to geometrical changes in the sub-Angstrom range.

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.

The fifth harmonic (162 nm, 11 fs), generated in a short argon cell from 12 fs Ti-sapphire laser pulses, was used to excite C2H4 and C2D4 in the maximum of the first pi pi* transition. Around 10% of the molecules were excited to the pi3s Rydberg state instead. The subsequent motion of the wave packet, moving over the potentials from the Franck-Condon region down to the ground state, was monitored by nonresonant ionization at 810 nm with mass-selective detection of the ion yield. Five time constants (from approximately 20 fs in excited states to 0.6-11 ps in the hot ground state) and four coherent oscillations (CC stretch and torsion vibrations or hindered free rotation) were determined for each isotopomer. The initial relaxation follows a superposition of CC twist and stretch coordinates; this explains a surprisingly small deuterium isotope effect of the initial time constant (21 versus 24 fs). Also the vibrations in the Franck-Condon region have such a mixed character and a correspondingly small isotope shift. From the perpendicular minimum the wave packet reaches (within 17 or 21 fs for the two isotopomers) a conical intersection via a direction that also involves partial hydrogen migration. This is concluded from the detection of ethylidene (CH3CH), formed simultaneously with ground-state ethylene. This carbene isomerizes in the ground state within 0.6 ps (1.6 ps for CD3CD) to ethylene. Two time constants for dissociation (4.5 and 11 ps) in the hot ground state were also identified. The small yields of bimolecular reactions (photodimerization, addition reactions involving a "suddenly polarized" excited state, carbene reactions) are interpreted in terms of the short lifetimes. It is pointed out that the relaxation path starting from the Rydberg state merges into that from the pi pi* state; nevertheless, there is a wavelength dependence in the photochemistry of olefins, because due to a momentum effect the wave packet remembers from which state it came.

Self-focusing of few-cycle pulses in atmospheric-pressure argon results in a supercontinuum which differs remarkably from the case of longer pulses: under single-filament conditions it extends to 200 nm and 250 nm with 6 fs and 10 fs pulses, respectively; the radiation, including the shortest wavelengths, is collimated and shows no conical emission. The short-wavelength part is intrinsically at least as short as the incoming fundamental pulse. These features make the few-cycle supercontinuum attractive as a source of widely tunable 10 fs pump pulses for spectroscopic applications. We present extensive experimental results including the dependence of the spectrum on pulse energy, duration and chirp, filament length, gas pressure and a comparison with nitrogen and air. We discuss them and other features including the role of the third harmonic and identify the conditions required to get a single highly stable filament. We also present a model, based on self-guiding, which predicts useful scaling rules.

Dose limiting side effects of interleukin-2 (IL-2) include severe hypotension and vascular leak syndrome (VLS). Previous studies have shown that nitric oxide (NO) synthesis is strongly induced after IL-2 treatment of C3H/HeN mice (180,000 IU b.i.d. for 5 d). We employed knockout mice (on C57BL/6 background) to test the role of the inducible NO synthase (iNOS) in mediating IL-2 toxicity. In contrast to C3H/HeN mice, which developed hypotension and VLS after 10 doses of only 180,000 IU IL-2, C57BL/6 mice were far more resistant requiring increased doses of 800,000 IU IL-2 (b.i.d., 5 d) to induce hypotension and VLS. Serum interferon-gamma levels were significantly more elevated by IL-2 treatment in C3H/HeN mice than in C57BL/6, correlating with the severity of hypotension and VLS. Urinary excretion of NO metabolites was markedly reduced in iNOS knockout mice (C57BL/6 iNOS) after IL-2 treatment. A surprising finding was that these mice still developed profound hypotension and VLS. Similar findings were observed after administration of a iNOS specific inhibitor, L-N[6]-(1-iminoethyl)lysine (L-NIL). In contrast, a general NOS inhibitor, N-monomethyl-L-arginine, prevented both hypotension and vascular leak. The superoxide dismutase mimetic, M40403, reversed IL-2-induced hypotension but not VLS in knockout mice. Thus, peroxynitrite-mediated mechanisms are likely responsible for hypotension, whereas NO-induced changes in vascular permeability result in VLS. The iNOS enzyme is not necessary for pathogenesis of IL-2-induced cardiovascular toxicity. These results imply that other NOS isoforms, such as endothelial NOS, may play a major role in the development of IL-2-induced cardiovascular toxicity.

In the group-6 metal hexacarbonyls a number of metal-to-ligand charge-transfer (MLCT) and ligand-field (LF or d → d) states can be excited in the near UV. The latter are repulsive. In equilibrium geometry, most of them are higher than the MLCT states. We probed the dynamics of photodissociation of M(CO) 6 → M(CO) 5 + CO (M = Cr; some data also for M = Mo) with improved time resolution (10–40 fs), pumping at different wavelengths (mainly 270–345 nm) and probing by nonresonant photoionization. The initial relaxation (e.g. within 12.5 fs from T 1u excited at 270 nm) is assigned to direct crossing over to the repulsive surface, from where the subsequent dissociation is also remarkably fast (18 fs in this example). That is, there is no detour via the lowest excited singlet state, in contrast to the usual assumption. Also with 318 and 345 nm excitation a direct MLCT → LF relaxation seems to occur before dissociation. The product M(CO) 5 is generated in the S 1 state, also at pump wavelengths (345 nm) with barely sufficient energy. It relaxes to S 0 through a Jahn–Teller induced conical intersection along pseudorotation coordinates, which stimulates a coherent oscillation in S 0 in this vibration. A higher-frequency oscillation, assigned to totally symmetric MC stretch vibrations, is already found in the Franck–Condon region; it persists (with different wavenumbers) also during dissociation and over the subsequent product states. This vibration is transverse to the valley of dissociation, which is barrierless. The wavelength-independent mechanism also implies that there is no triplet contribution (which was previously supposed at long wavelengths) to photochemical dissociation of the hexacarbonyls.

Brain metastases are a frequent complication of advanced melanoma. Neurosurgery (generally followed by radiotherapy) may be useful in managing solitary, superficial brain metastases in good performance status patients, as well as for diagnostic purposes. Since most patients are not felt to be resectable and concurrent extracranial metastases frequently are present, whole-brain radiotherapy (WBRT) has become the de facto treatment standard. WBRT has resulted in disappointing outcomes, resulting in a 3.6-4.1-month median survival. Recent studies have suggested that focal irradiation using linear accelerator-based stereotactic radiosurgery or gamma-knife technologies can result in excellent local control and prolonged survival in some patients. It is possible that more aggressive combined modality treatment strategies, such as addition of systemic therapy, may further improve outcome. Current data suggest that aggressive treatment of patients with up to five brain melanoma brain metastases is capable of producing prolonged survival in many patients, including some long-term complete responses.

Brain metastases seem to be an almost inevitable complication in patients with metastatic melanoma. Except for the rare patients who can undergo successful surgical resection of brain metastases, current management strategies do not appear adequate and result in a poor outcome (median survival, 2-4 months). In recent small series, stereotactic radiosurgery or gamma-knife treatment has suggested improvement in local control compared with whole brain radiation therapy. We have recently shown prolonged survival (11.1 months) using a multimodality treatment approach in 44 sequential patients with melanoma brain metastases. A subsequent study demonstrated that the outcome of biochemotherapy for metastatic melanoma is not affected by the presence or absence of brain metastases. Our results suggest that the outcome of patients with melanoma brain metastases can be improved using a multidisciplinary management strategy.

Purpose To compare the overall survival (OS) of patients with resected stage III melanoma administered active specific immunotherapy and low-dose interferon alfa-2b (IFN-α-2b) with the OS achieved using high-dose IFN-α-2b. Patients and Methods An Ad Hoc Melanoma Working Group of 25 investigators treated 604 patients from April 1997 to January 2003. Patients were stratified by sex and number of nodes and were randomly assigned to receive either 2 years of treatment with active specific immunotherapy with allogeneic melanoma lysates and low-dose IFN-α-2b (arm 1) or high-dose IFN-α-2b alone for 1 year (arm 2). Active specific immunotherapy was injected subcutaneously (SC) weekly for 4 weeks, at week 8, and bimonthly thereafter. IFN-α-2b SC was begun on week 4 and continued thrice weekly at 5 MU/m2 for 2 years. IFN-α-2b in arm 2 was administered according to the Eastern Cooperative Oncology Group 1684 study regimen. Results Median follow-up time was 32 months for all patients and 42 months for surviving patients. Median OS time exceeds 84 months in arm 1 and is 83 months in arm 2 (P = .56). Five-year OS rate is 61% in arm 1 and 57% in arm 2. Estimated 5-year relapse-free survival (RFS) rate is 50% in arm 1 and 48% in arm 2, with median RFS times of 58 and 50 months, respectively. The incidence of serious adverse events as a result of treatment was the same in both arms, but more severe neuropsychiatric toxicity was seen in arm 2. Conclusion OS and RFS achieved by active specific immunotherapy and low-dose IFN-α-2b were indistinguishable from those achieved by high-dose IFN-α-2b. Long RFS and OS times were observed in both treatment arms.

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.

In metastatic renal cell carcinoma (mRCC), survival benefit associated with objective response rates of 16–20 % with high-dose interleukin-2 (HDIL-2) is well established and discussed. Based on recently emerged data on efficacy of cancer immunotherapy, we hypothesized that the survival benefit with HDIL-2 extends beyond those achieving objective responses, i.e., to those who achieve stable disease as the best response to treatment. All sequential treatment naive mRCC patients treated with HDIL-2 at the University of Utah (1988–2013) and University of Michigan (1997–2013) were included. Best responses on treatment were associated with survival outcomes using log-rank and COX regression with a landmark analysis at 2 months. 391 patients (75 % male; median age 55 years) were included and belonged to the following prognostic risk categories: 20 % good, 64 % intermediate, and 15 % poor. Best responses on treatment were complete response (9 %), partial response (10 %), stable disease (32 %), progressive disease (42 %), and not evaluable for response (7 %). No significant differences in progression-free survival (HR 0.74, 95 % CI 0.48–1.1, p = 0.14) or overall survival (HR 0.66, 95 % CI 0.39–1.09, p = 0.11) were observed between patients achieving partial response versus stable disease. Significant differences in progression-free survival (HR 0.13, 95 % CI 0.09–0.22, p

Purpose: Brain metastases of melanoma, renal carcinoma, and sarcoma have traditionally responded poorly to conventional treatments, including surgery and whole-brain radiotherapy (WBRT). Several studies have suggested a beneficial effect of stereotactic radiosurgery (SRS). We evaluated our institutional experience with systematic SRS in patients harboring these “radioresistant” metastases. Methods and Materials: A total of 68 patients with brain metastases from melanoma, renal carcinoma, and sarcoma underwent SRS with or without WBRT or surgical resection. All patients had Karnofsky performance scores >70, and SRS was performed before the initiation of systemic therapy. The survival time was calculated from the diagnosis of brain metastases using the Kaplan-Meier product-limit method. Statistical significance was calculated using the log–rank test. Factors influencing survival, including surgical resection, WBRT, gender, number of SRS sessions, and histologic type, were evaluated retrospectively using Cox univariate models. Results: The overall median survival was 427 days (14.2 months), which appears superior to the results obtained with conventional WBRT. The addition of neither surgery nor WBRT to SRS provided a statistically significant increase in survival. Conclusion: Our results suggest that patients undergoing SRS for up to five cerebral metastases from “radioresistant” tumors (melanoma, renal cell carcinoma, and sarcoma) have survival rates comparable to those in other series of more selected patients. The addition of surgical resection or WBRT did not result in improved survival in our series.

ReGel is an aqueous, filter sterilizable ABA tri-block polymer consisting of poly-(lactide-co-glycolide) and polyethylene glycol. We tested the suitability of this polymer to provide sustained interleukin-2 (IL-2) delivery for cancer immunotherapy. ReGel/IL-2 is liquid at or below room temperature, and is easily injectable through narrow gauge needles, but undergoes a reversible thermal transition into a bioerodible depot at body temperature. We demonstrated that ReGel/IL-2 releases IL-2 over 72 to 96 hours in vitro, without loss of bioactivity. Pharmacokinetic studies after peritumoral injection of 0.1 mL ReGel/IL-2 in mice demonstrated an early burst of IL-2 release, followed by more sustained release kinetics over 96 hours (T(1/2)beta 48 h). Less than 1.5% of the injected dose was detectable in blood or kidneys during the first 48 hours. A single peritumoral dose of ReGel/IL-2 [1 to 4 million international units (MIU) ReGel/IL-2, split into 4 quadrant injections] was administered to mice bearing subcutaneous RD-995 spindle cell carcinoma. Only the highest dose of ReGel/IL-2 tested (4.0 MIU) resulted in significant hypotension on day 3 after injection. Weekly treatment of Meth A fibrosarcoma and RENCA renal carcinoma with ReGel/IL-2 (2 MIU/dose) induced a significant reduction in tumor growth and improved survival. Reduction in tumor growth at implants remote from treated lesions was also observed, suggesting systemic activation of antitumor immunity. These findings establish that peritumoral injection of ReGel/IL-2 is an effective delivery system for cancer immunotherapy, while decreasing IL-2 toxicity. This polymer delivery system is likely to be broadly applicable for sustained delivery of other cytokines and peptides.

Focusing 800-nm pulses of 10–20 fs and ≤0.4 mJ into atmospheric-pressure argon gives rise to a supercontinuum extending down to 250 nm. We show that spectral cuts from this radiation can be shortened by a simple prism compressor down to 30 fs even near the UV cut-off. The resulting pulses have enough energy (several hundred nanojoules) to serve as a simple and rugged broadly tunable pump source in ultra-fast transient spectroscopy. Such an application is demonstrated for the first time, using pulses tuned over 280–320 nm to excite Cr(CO)6; probing it by intense-field ionization at 800 nm, we determine the lifetime of initially populated states to be as short as 14 fs.

Photochemically, s-cis-dienes can undergo cis-trans isomerization or electrocyclic ring closure to cyclobutenes. Modern quantum chemistry predicts that both reactions can originate from the same conical intersection and explains thereby why photochemical ring opening of cyclobutenes to dienes is often not stereospecific, although ring closure of dienes is. Evidence is found that the reaction path already branches earlier, investigating two cyclic dienes which were excited by a femtosecond UV pulse in the gas phase and probed by photoionization at 810 nm. The multistep path is assigned to the excited-state surfaces and ring closure of the ground-state trans isomers is also detected.

Purpose Familial melanoma patients are reported to present with thinner melanomas, to be younger at the time of diagnosis, and to have a greater likelihood of developing multiple primary tumors. We sought to determine whether melanomas that occur in a familial setting demonstrate different prognostic and survival statistics relative to sporadic melanoma. Patients and Methods This population-based study used the Utah Cancer Registry and Utah Population Database to objectively evaluate prognostic and survival statistics of the familial melanoma population. From 1973 to 1999, there were 7,785 cases of invasive melanoma identified through the Utah Cancer Registry. These were linked to the Utah Population Database, resulting in 2,659 subjects with family-history information from which a familiality score could be calculated. Cases scored in the top ninth percentile were assigned as high familial risk, and the remaining 91% were considered low familial risk. Results Multivariate logistic-regression analysis found no association between sex, Breslow depth, Clark level, or survival and the familial status. Age at first diagnosis of invasive melanoma was slightly lower in the high-familial-risk group (57 v 60 years; P = .03). High-familial-risk subjects had more melanomas diagnosed at age 30 or younger (12% v 6%; P < .001). A significant difference in the overall number of individuals with two or more primary malignant melanomas was not detected among the groups (P = .2). Conclusion These data suggest that melanomas occurring in the context of an underlying inherited susceptibility do not have a significantly different biologic behavior.

Probing by dissociative intense-laser field ionization, we found that cyclopentadiene relaxes from the initial 1B 2 state, excited at 240 nm, within 37 fs to the dark 2A 1 state; a doubly exponential decay (71 and 333 fs) leads from there to S 0 . To explain the short times, we invoke conical intersections which we associate with photochemical pericyclic reactions: electrocyclization and a hydrogen shift. The latter reaction is dominant, as concluded from the deuterium isotope effect. A reaction (19 ps) found after departure from 2A 1 is ascribed to thermal back reaction of the initially formed electrocyclization product bicyclo[2,1,0]pentene in the hot ground state, recovering cyclopentadiene. Comparing this molecule with two others, benzene and cycloheptatriene, we point out that ultrafast internal conversion is not governed by densities of states and matrix elements, but by the pathway on potential surfaces; the matrix-element approach tacitly assumes vertical transitions. But probably ultrafast radiationless transitions are always accompanied by large displacements of atoms or groups similar to that in chemical reactions, so that photophysics is a consequence of photochemistry in such cases. Both have the initial path in common, typically till the last conical intersection.

Purpose The nucleoside analog 5-aza-2′-deoxycytidine (5-aza-CdR, decitabine) is a potent inhibitor of DNA methylation in vitro. Cellular treatment with this agent induces the re-expression of methylation-silenced genes. It remains unclear to what extent this compound inhibits DNA methylation in vivo. A clinical study was designed to examine the molecular effects and toxicity of a continuous 1-week intravenous infusion of decitabine in solid tumor patients. Methods Ten patients with refractory solid tumors were included in this study. Decitabine was administered at 2 mg/m2/d via continuous infusion for 168 hours. Quantitative polymerase chain reaction and high performance liquid chromatography were utilized to measure promoter-specific and global DNA methylation in peripheral-blood cells before and after treatment. Results Transient grade III/IV neutropenia (two patients) and grade II thrombocytopenia (one patient) was observed at the lowest planned dose step (2 mg/m2/d for 7 days). Nonhematologic toxicities were not observed. Quantitative polymerase chain reaction demonstrated significant MAGE-1 promoter hypomethylation by 14 days after the start of treatment in all 13 treatment cycles examined. Significant genomic DNA hypomethylation was also seen by day 14 in 11 of 13 treatment cycles analyzed. Genomic DNA methylation reverted to baseline levels by 28 to 35 days after the start of treatment, demonstrating that inhibition of DNA methylation by decitabine is transient. Conclusion A 168-hour continuous infusion of decitabine is well tolerated and results in the inhibition of promoter-specific and genomic DNA methylation in vivo. This treatment schedule is suitable for evaluation of decitabine in combination with agents whose activity may be enhanced by the reversal of DNA methylation–mediated gene silencing.

Ten femtosecond pulses at 805 nm with energy up to 1 mJ were produced by self-phase modulation of 45-fs pulses in Ar at atmospheric pressure and subsequent compression by chirped mirrors. Focusing part of this radiation again into Ar at atmospheric pressure generates a single filament with broadband emission covering the range from > 1000 to 250 nm. This range extends farther into the UV than previously observed with such low energies, overlapping even the region of the third harmonic. Only a small fraction of the power is contained outside the central spot. Using a simple prism compressor, pulses were obtained with durations of 70 fs and energies of 700 nJ in the range 270–290 nm.

We investigated dissociative single and double ionization of the metal carbonyls Ni(CO)4, Fe(CO)5 and Cr(CO)6 in the gas phase by means of laser pulses of different durations (30–110 fs) and wavelengths (0.8 and 1.35 µm) at intensities of 2 × 1012–2 × 1014 W cm−2. The mass spectra show striking differences: for example, Fe(CO)5 strongly fragments at 0.8 µm but little at 1.35 µm, whereas for Ni(CO)4 fragmentation is higher at 1.35 µm than at 0.8 µm; chromium carbonyl shows little fragmentation at both wavelengths. In other cases, fragmentation first decreases and then increases again with intensity. These and other phenomena, also published ones, can readily be understood from long-known principles, namely resonances in the parent ions, sometimes also in the neutral molecules, in particular if relaxations are also taken into account. We emphasize that fragmentation and ionization are two separate processes. We also point out that in the process of dissociative ionization in intense laser radiation, one should generally consider intermediate states, even if there is no one-photon resonance.

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.

Purpose: The purpose of this phase II multi-institutional study was to define the efficacy and toxicity of infusional 5-FU in combination with PALA and leucovorin in patients with advanced pancreatic cancer. Patients and methods: Patients were required to have histologically confirmed pancreatic cancer that was locally advanced, unresectable or disseminated. The treatment regimen consisted of weekly 5-FU 2600 mg/m2 given concurrently with leucovorin at 500 mg/m2. Both drugs were administered by 24-hour continuous infusion. PALA was administered 24 hours prior to the administration of 5-FU/LV at a dose of 250 mg/m2 IV over 15 minutes weekly. Patients were continued on the assigned treatment regimen until progression of disease, unacceptable toxicity, or the patient declined further therapy. Results: This study accrued 30 patients. Four of these patients were ineligible. All 26 eligible patients were evaluated for toxicity. One patient had inadequate assessment of response and was considered a non-responder. Three of the twenty-six eligible patients had partial responses, for a response rate of 12% (95% confidence interval 2% to 30%). All 26 eligible patients have died and the median overall survival was 7 months (95% confidence interval: 5.2 to 9 months). Four patients experienced grade 4 toxicities, including bilirubin increase (2 patients), vomiting (1 patient) and non-local skin ulceration (1). Two patients discontinued therapy due to toxicity. Conclusion: The dual modulation of 5-FU with PALA and leucovorin in the dose and schedule used here, has a response rate similar to other single agents in pancreatic cancer and can result in some long term survival while having relatively mild toxicity.

Objectives . To evaluate response rates, progression-free survival (PFS), overall survival (OS), and toxicity of two high-dose chemotherapy regimens with stem cell rescue used to treat patients with recurrent or persistent stage III/IV ovarian cancer, with the goal of taking one forward into a Phase III comparison with conventional therapy. Methods . Patients under 65 with clinically or pathologically persistent disease after initial chemotherapy or those relapsing >6 months after a complete remission (CR) were randomized to CMC carboplatin (1500 mg/m 2 ), mitoxantrone (75 mg/m 2 ), and cyclophosphamide (120 mg/kg)], or CTC: [cisplatin (165 mg/m 2 ), thiotepa (600 mg/m 2 ), and cyclophosphamide (5625 mg/m 2 )] with stem cell rescue. Results . Of 67 randomized, the 32 and 26 eligible in the CMC and CTC arms were matched including age (median 49), maximum tumor diameter, and disease status at transplant. Low-risk disease (maximum diameter disease ≤ 0.5 cm and platinum sensitivity) was demonstrated in only approximately one-half of the patients. There were two treatment-related deaths in each arm. The median PFS was 13 and 8 months, respectively, for the CMC and CTC arms. The median OS was 29 and 22 months for the CMC and CTC arms. In a multivariate analysis of PFS, normal CA125 at transplant and CR to primary therapy were significant; for OS, normal CA125 and platinum sensitivity were significant. Conclusions . The CMC regimen was the superior regimen. However, few patients were long-term progression-free survivors. A clinical CR to primary therapy and a normal CA125, seen in a minority of patients, were requirements for a favorable outcome.

Cis-stilbene was excited by one photon at 270 nm in the gas phase and then probed by ionization at infrared wavelengths (810 and 2100 nm), recording the delay-time dependent mass spectra. We found not only a decay of 300 fs, previously assigned to departure from the fluorescent region, but also a second time constant (160 fs), probably representing departure from the ‘perpendicular minimum’ (excited state with twisted ethene part). In addition, two coherent oscillations (periods 140 and ≈600 fs) were found in the 300-fs window. We discuss their implications for the initial motion and point out the importance of vibronic interaction of excited states.