Adjuvant Therapy of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Patients With Resected Stage IIIB-D or Stage IV Melanoma (CheckMate 915)

Teràpia adjuvant; MelanomaTerapia adyuvante; MelanomaAdjuvant therapy; MelanomaPURPOSE Ipilimumab and nivolumab have each shown treatment benefit for high-risk resected melanoma. The phase III CheckMate 915 trial evaluated adjuvant nivolumab plus ipilimumab versus nivolumab alone in patients with resected stage IIIB-D or IV melanoma. PATIENTS AND METHODS In this randomized, double-blind, phase III trial, 1,833 patients received nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks (916 patients) or nivolumab 480 mg once every 4 weeks (917 patients) for ≤ 1 year. After random assignment, patients were stratified by tumor programmed death ligand 1 (PD-L1) expression and stage. Dual primary end points were recurrence-free survival (RFS) in randomly assigned patients and in the tumor PD-L1 expression-level < 1% subgroup. RESULTS At a minimum follow-up of approximately 23.7 months, there was no significant difference between treatment groups for RFS in the all-randomly assigned patient population (hazard ratio, 0.92; 95% CI, 0.77 to 1.09; P = .269) or in patients with PD-L1 expression < 1% (hazard ratio, 0.91; 95% CI, 0.73 to 1.14). In all patients, 24-month RFS rates were 64.6% (combination) and 63.2% (nivolumab). Treatment-related grade 3 or 4 adverse events were reported in 32.6% of patients in the combination group and 12.8% in the nivolumab group. Treatment-related deaths were reported in 0.4% of patients in the combination group and in no nivolumab-treated patients. CONCLUSION Nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks did not improve RFS versus nivolumab 480 mg once every 4 weeks in patients with stage IIIB-D or stage IV melanoma. Nivolumab showed efficacy consistent with previous adjuvant studies in a population resembling current practice using American Joint Committee on Cancer eighth edition, reaffirming nivolumab as a standard of care for melanoma adjuvant treatment

MORFOLOGÍA POLÍNICA DE CINCO ESPECIES DE LA SUBFAMILIA CACTOIDEAE (FAM: CACTACEAE), DEL DEPARTAMENTO DE LIMA (PERÚ)

Se describieron las características morfológicas de los granos de polen de cinco especies pertenecientes a la familia Cactaceae, subfamilia Cactoideae: Tres especies, Echinopsis chalaensis (Rauh & Backeb.) Friedrich & G.D. Rowley, Haageocereus decumbens (Vaupel) Backeb. y Pygmaeocereus sp. Johnson & Backeb., (tribu Trichocereeae); Corryocactus brevistylus (K. Schum. ex Vaupel) Britton & Rose (tribu Pachycereeae) y Neoraimondia arequipensis (Meyen) Backeb. (tribu Browningieae). Todos los granos de polen fueron observados con microscopio óptico (MO), estos se presentaron en mónadas, la forma varió de esferoidal a oblato esferoidal, siendo todos colpados, excepto C. brevistylus, con espínulas que van desde menos de 1 µm hasta los 2 µm, el grosor de la exina varía entre 2 y 3 µm, no se aprecian mucha diferencia del tectum, el cual siempre es perforado. Se presenta una clave para diferenciar las especies estudiadas

Randomized crossover pharmacokinetic evaluation of subcutaneous versus intravenous granisetron in cancer patients treated with platinum-based chemotherapy

BACKGROUND: 5-HT3-receptor antagonists are one of the mainstays of antiemetic treatment, and they are administered either i.v. or orally. Nevertheless, sometimes neither administration route is feasible, such as in patients unable to admit oral intake managed in an outpatient setting. Our objective was to evaluate the bioavailability of s.c. granisetron. PATIENTS AND METHODS: Patients receiving platinum-based chemotherapy were randomized to receive 3 mg of granisetron either s.c. or i.v. in a crossover manner during two cycles. Blood and urine samples were collected after each cycle. Pharmacokinetic parameters observed with each administration route were compared by analysis of variance. RESULTS: From May to November 2005, 31 patients were included and 25 were evaluable. Subcutaneous granisetron resulted in a 27% higher area under the concentration-time curve for 0-12 hours (AUC(0-12h)) and higher levels at 12 hours, with similar values for AUC(0-24h). The maximum concentration was lower with the s.c. than with the i.v. route and was observed 30 minutes following s.c. administration. CONCLUSION: Granisetron administered s.c. achieves complete bioavailability. This is the first study that shows that s.c. granisetron might be a valid alternative to i.v. delivery. Further trials to confirm clinical equivalence are warranted. This new route of administration might be especially relevant for outpatient management of emesis in cancer patients

Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Outcomes in histopathologic subgroups from the randomized, double-blind, phase 3 KEYNOTE-716 trial

Background Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study of resected stage IIB or IIC melanoma. At the prespecified third interim analysis (data cut-off, January 4, 2022), the HR for RFS in the overall population was 0.64 (95% CI, 0.50 to 0.84) and the HR for DMFS was 0.64 (95% CI, 0.47 to 0.88). We present a post hoc analysis of efficacy by subtypes defined by histopathologic characteristics. Methods Patients aged ≥ 12 years with newly diagnosed, resected stage IIB or IIC melanoma were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. The primary end point was RFS per investigator review; DMFS per investigator review was secondary. Subgroups of interest were melanoma subtype (nodular vs non-nodular), tumor thickness ( ≤ 4 mm vs \u3e 4 mm), presence of ulceration (yes vs no), mitotic rate ( \u3c 5 per mm 2 (median) vs ≥ 5 per mm 2), and presence of tumor-infiltrating lymphocytes (TILs; absent vs present). Results Between September 23, 2018, and November 4, 2020, 976 patients were assigned to pembrolizumab (n=487) or placebo (n=489). Median follow-up was 27.4 months (range, 14.0-39.4). The HR (95% CI) for RFS was 0.54 (0.37 to 0.79) for nodular and 0.77 (0.53 to 1.11) for non-nodular melanoma; 0.57 (0.37 to 0.89) for thickness ≤ 4 mm and 0.69 (0.50 to 0.96) for \u3e 4 mm; 0.66 (0.50 to 0.89) for ulceration and 0.57 (0.32 to 1.03) for no ulceration; 0.57 (0.35 to 0.92) for mitotic rate \u3c 5 per mm 2 and 0.57 (0.40 to 0.80) for ≥ 5 per mm 2; and 0.89 (0.52 to 1.54) for TILs absent and 0.51 (0.34 to 0.76) for TILs present. DMFS results were similar. In a Cox multivariate analysis, treatment arm, tumor thickness, and mitotic rate were significant independent factors for RFS, and treatment arm and mitotic rate were significant independent factors for DMFS. Conclusions In this post hoc analysis, the benefit of pembrolizumab was largely consistent with the overall study population regardless of histopathologic characteristics. These results support the use of adjuvant pembrolizumab in patients with resected stage IIB or IIC melanoma. Trial registration number ClinicalTrials.gov, NCT03553836

Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Outcomes in histopathologic subgroups from the randomized, double-blind, phase 3 KEYNOTE-716 trial

Background: Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study of resected stage IIB or IIC melanoma. At the prespecified third interim analysis (data cut-off, January 4, 2022), the HR for RFS in the overall population was 0.64 (95% CI, 0.50 to 0.84) and the HR for DMFS was 0.64 (95% CI, 0.47 to 0.88). We present a post hoc analysis of efficacy by subtypes defined by histopathologic characteristics. Methods: Patients aged ≥12 years with newly diagnosed, resected stage IIB or IIC melanoma were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. The primary end point was RFS per investigator review; DMFS per investigator review was secondary. Subgroups of interest were melanoma subtype (nodular vs non-nodular), tumor thickness (≤4 mm vs >4 mm), presence of ulceration (yes vs no), mitotic rate (<5 per mm$^{2}$(median) vs ≥5 per mm$^{2}$), and presence of tumor-infiltrating lymphocytes (TILs; absent vs present). Results: Between September 23, 2018, and November 4, 2020, 976 patients were assigned to pembrolizumab (n=487) or placebo (n=489). Median follow-up was 27.4 months (range, 14.0–39.4). The HR (95% CI) for RFS was 0.54 (0.37 to 0.79) for nodular and 0.77 (0.53 to 1.11) for non-nodular melanoma; 0.57 (0.37 to 0.89) for thickness ≤4 mm and 0.69 (0.50 to 0.96) for >4 mm; 0.66 (0.50 to 0.89) for ulceration and 0.57 (0.32 to 1.03) for no ulceration; 0.57 (0.35 to 0.92) for mitotic rate <5 per mm$^{2}$and 0.57 (0.40 to 0.80) for ≥5 per mm$^{2}$; and 0.89 (0.52 to 1.54) for TILs absent and 0.51 (0.34 to 0.76) for TILs present. DMFS results were similar. In a Cox multivariate analysis, treatment arm, tumor thickness, and mitotic rate were significant independent factors for RFS, and treatment arm and mitotic rate were significant independent factors for DMFS. Conclusions: In this post hoc analysis, the benefit of pembrolizumab was largely consistent with the overall study population regardless of histopathologic characteristics. These results support the use of adjuvant pembrolizumab in patients with resected stage IIB or IIC melanoma. Trial registration number: ClinicalTrials.gov,NCT03553836

Adjuvant pembrolizumab versus placebo in resected high-risk stage II melanoma: Health-related quality of life from the randomized phase 3 KEYNOTE-716 study

Background: Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) versus placebo in resected stage IIB and IIC melanoma in the phase 3 KEYNOTE-716 study. Health-related quality of life (HRQoL) results are reported. Methods: Patients were randomly assigned 1:1 to pembrolizumab 200 mg (2 mg/kg, patients ≥ 12 to \u3c 18 years) Q3W or placebo for ≤ 17 cycles or until disease recurrence, unacceptable toxicity, or withdrawal. Change from baseline in EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) was a prespecified exploratory end point. Change in EORTC QLQ-C30 functioning, symptom, and single-item scales, and EQ-5D-5L visual analog scale (VAS) were also summarized. Primary analyses were performed at week 48 to ensure adequate completion/compliance. The HRQoL population comprised patients who received ≥ 1 dose of treatment and completed ≥ 1 assessment. Results: The HRQoL population included 969 patients (pembrolizumab, n = 483; placebo, n = 486). Compliance at week 48 was ≥ 80 % for both instruments. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores were stable from baseline to week 48 in both arms, with no clinically meaningful decline observed. Scores did not differ significantly between pembrolizumab and placebo. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores remained stable through week 96 in both arms. Conclusions: HRQoL was stable with adjuvant pembrolizumab, with no clinically meaningful decline observed. Change from baseline in HRQoL was similar between arms. These results, in conjunction with the improved RFS and manageable safety previously reported, support the use of adjuvant pembrolizumab for high-risk stage II melanoma

Development of a few TW Ti:Sa laser system at 100 Hz for proton acceleration

[EN] We report the development of a table-top high peak power Titanium:Sapphire (Ti:Sa) CPA laser working at 100 Hz capable of delivering 205 mJ, 55 fs pulses. Every amplification stage is pumped by Nd-doped solid-state lasers and fully powered by diodes. Thermal effects in the Ti:Sa amplifiers are compensated passively with optics. This system is intended to be used for proton acceleration experiments at high repetition rates.Centro para el Desarrollo Tecnológico Industrial (CDTI, Spain) within the INNPRONTA program, Grant no. IPT-20111027.Lera, R.; Bellido-Millán, PJ.; Sánchez, I.; Mur, P.; Seimetz, M.; Benlloch Baviera, JM.; Roso, L.... (2019). Development of a few TW Ti:Sa laser system at 100 Hz for proton acceleration. Applied Physics B. 125(1):1-8. https://doi.org/10.1007/s00340-018-7113-8S181251P. Zeitoun, G. Faivre, S. Sebban, T. Mocek, A. Hallou, M. Fajardo, D. Aubert, P. Balcou, F. Burgy, D. Douillet, S. Kazamias, G. de Lachèze-Murel, T. Lefrou, S. le Pape, P. Mercère, H. Merdji, A.S. Morlens, J.P. Rousseau, C. Valentin, Nature 431(7007), 426–429 (2004)V. Malka, S. Fritzler, E. Lefebvre, M.-M. Aleonard, F. Burgy, J.-P. Chambaret, J.-F. Chemin, K. Krushelnick, G. Malka, S.P.D. Mangles, Z. Najmudin, M. Pittman, J.-P. Rousseau, J.-N. Scheurer, B. Walton, A.E. Dangor, Science 298(5598), 1596–1600 (2002)H. Daido, M. Nishiuchi, A.S. Pirozhkov, Rep. Progress Phys. 75(5), 056401 (2012)A. Macchi, M. Borghesi, M. Passoni, Rev. Mod. Phys. 85, 751–793 (2013)T. Tajima, J.M. Dawson, Phys. Rev. Lett. 43, 267–270 (1979)M. Noaman-ul Haq, H. Ahmed, T. Sokollik, L. Yu, Z. Liu, X. Yuan, F. Yuan, M. Mirzaie, X. Ge, L. Chen, J. Zhang, Phys. Rev. Accel. Beams 20, 041301 (2017)D. Strickland, G. Mourou, Opt. Commun. 53(3), 219–221 (1985)G. Cheriaux, B. Walker, L.F. Dimauro, P. Rousseau, F. Salin, J.P. Chambaret, Opt. Lett. 21(6), 414–416 (1996)P. Tournois, Opt. Commun. 140(4), 245–249 (1997)R. Soulard, A. Brignon, S. Raby, E. Durand, R. Moncorgé, Appl. Phys. B 106(2), 295–300 (2012)J. Liu, L. Ge, L. Feng, H. Jiang, H. Su, T. Zhou, J. Wang, Q. Gao, J. Li, Chin. Opt. Lett. 14(5), 051404 (2016)A. Maleki, M.K. Tehrani, H. Saghafifar, M.H.M. Dindarlu, H. Ebadian, Laser Phys. 26(2), 025003 (2016)R. Lera, F. Valle-Brozas, S. Torres-Peiró, A.R. de-la Cruz, M. Galán, P. Bellido, M. Seimetz, J.M. Benlloch, L. Roso, Appl. Opt. 55(33), 9573–9576 (2016)R. Lausten, P. Balling, J. Opt. Soc. Am. B 20(7), 1479–1485 (2003)I. Nam, M. Kim, T.H. Lee, S.W. Lee, H. Suk, Curr. Appl. Phys. 15(4), 468–472 (2015)E. Treacy, IEEE J. Quantum Electron. 5(9), 454–458 (1969)A. Trisorio, S. Grabielle, M. Divall, N. Forget, C.P. Hauri, Opt. Lett. 37(14), 2892–2894 (2012)Y.-H. Cha, Y.-W. Lee, S.M. Nam, J.M. Han, Y.J. Rhee, B.D. Yoo, B.C. Lee, Y.U. Jeong, Appl. Opt. 46(28), 6854–6858 (2007)P. Bellido, R. Lera, M. Seimetz, A.R. de la Cruz, S. Torres-Peiró, M. Galán, P. Mur, I. Sánchez, R. Zaffino, L. Vidal, A. Soriano, S. Sánchez, F. Sánchez, M. Rodríguez-Álvarez, J. Rigla, L. Moliner, A. Iborra, L. Hernández, D. Grau-Ruiz, A. González, J. García-Garrigos, E. Díaz-Caballero, P. Conde, A. Aguilar, L. Roso, J. Benlloch, J. Instrum. 12(05), T05001 (2017

Adjuvant Therapy of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Patients With Resected Stage IIIB-D or Stage IV Melanoma (CheckMate 915)

PURPOSE Ipilimumab and nivolumab have each shown treatment benefit for high-risk resected melanoma. The phase III CheckMate 915 trial evaluated adjuvant nivolumab plus ipilimumab versus nivolumab alone in patients with resected stage IIIB-D or IV melanoma. PATIENTS AND METHODS In this randomized, double-blind, phase III trial, 1,833 patients received nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks (916 patients) or nivolumab 480 mg once every 4 weeks (917 patients) for &lt;= 1 year. After random assignment, patients were stratified by tumor programmed death ligand 1 (PD-L1) expression and stage. Dual primary end points were recurrence-free survival (RFS) in randomly assigned patients and in the tumor PD-L1 expression-level &lt; 1% subgroup. RESULTS At a minimum follow-up of approximately 23.7 months, there was no significant difference between treatment groups for RFS in the all-randomly assigned patient population (hazard ratio, 0.92; 95% CI, 0.77 to 1.09; P = .269) or in patients with PD-L1 expression &lt; 1% (hazard ratio, 0.91; 95% CI, 0.73 to 1.14). In all patients, 24-month RFS rates were 64.6% (combination) and 63.2% (nivolumab). Treatment-related grade 3 or 4 adverse events were reported in 32.6% of patients in the combination group and 12.8% in the nivolumab group. Treatment-related deaths were reported in 0.4% of patients in the combination group and in no nivolumab-treated patients. CONCLUSION Nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks did not improve RFS versus nivolumab 480 mg once every 4 weeks in patients with stage IIIB-D or stage IV melanoma. Nivolumab showed efficacy consistent with previous adjuvant studies in a population resembling current practice using American Joint Committee on Cancer eighth edition, reaffirming nivolumab as a standard of care for melanoma adjuvant treatment

Bladder cancer index: cross-cultural adaptation into Spanish and psychometric evaluation

BACKGROUND: The Bladder Cancer Index (BCI) is so far the only instrument applicable across all bladder cancer patients, independent of tumor infiltration or treatment applied. We developed a Spanish version of the BCI, and assessed its acceptability and metric properties. METHODS: For the adaptation into Spanish we used the forward and back-translation method, expert panels, and cognitive debriefing patient interviews. For the assessment of metric properties we used data from 197 bladder cancer patients from a multi-center prospective study. The Spanish BCI and the SF-36 Health Survey were self-administered before and 12 months after treatment. Reliability was estimated by Cronbach's alpha. Construct validity was assessed through the multi-trait multi-method matrix. The magnitude of change was quantified by effect sizes to assess responsiveness. RESULTS: Reliability coefficients ranged 0.75-0.97. The validity analysis confirmed moderate associations between the BCI function and bother subscales for urinary (r = 0.61) and bowel (r = 0.53) domains; conceptual independence among all BCI domains (r ≤ 0.3); and low correlation coefficients with the SF-36 scores, ranging 0.14-0.48. Among patients reporting global improvement at follow-up, pre-post treatment changes were statistically significant for the urinary domain and urinary bother subscale, with effect sizes of 0.38 and 0.53. CONCLUSIONS: The Spanish BCI is well accepted, reliable, valid, responsive, and similar in performance compared to the original instrument. These findings support its use, both in Spanish and international studies, as a valuable and comprehensive tool for assessing quality of life across a wide range of bladder cancer patients

The Tree Biodiversity Network (BIOTREE-NET): prospects for biodiversity research and conservation in the Neotropics

Biodiversity research and conservation efforts in the tropics are hindered by the lack of knowledge of the assemblages found there, with many species undescribed or poorly known. Our initiative, the Tree Biodiversity Network (BIOTREE-NET), aims to address this problem by assembling georeferenced data from a wide range of sources, making these data easily accessible and easily queried, and promoting data sharing. The database (GIVD ID NA-00-002) currently comprises ca. 50,000 tree records of ca. 5,000 species (230 in the IUCN Red List) from \u3e2,000 forest plots in 11 countries. The focus is on trees because of their pivotal role in tropical forest ecosystems (which contain most of the world\u27s biodiversity) in terms of ecosystem function, carbon storage and effects on other species. BIOTREE-NET currently focuses on southern Mexico and Central America, but we aim to expand coverage to other parts of tropical America. The database is relational, comprising 12 linked data tables. We summarise its structure and contents. Key tables contain data on forest plots (including size, location and date(s) sampled), individual trees (including diameter, when available, and both recorded and standardised species name), species (including biological traits of each species) and the researchers who collected the data. Many types of queries are facilitated and species distribution modelling is enabled. Examining the data in BIOTREE-NET to date, we found an uneven distribution of data in space and across biomes, reflecting the general state of knowledge of the tropics. More than 90% of the data were collected since 1990 and plot size varies widely, but with most less than one hectare in size. A wide range of minimum sizes is used to define a \u27tree\u27. The database helps to identify gaps that need filling by further data collection and collation. The data can be publicly accessed through a web application at http://portal.biotreenet.com. Researchers are invited and encouraged to contribute data to BIOTREE-NET