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Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC.CheckMate 331 is a randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS).Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy [median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P = 0.11]. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase ≤ upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score ≥1% versus1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%.Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.

Immune checkpoint inhibitors are considered standard second-line treatment in advanced non-small cell lung cancer patients. This strategy has also become standard in first-line setting for a subgroup of patients with strongly positive PD-L1 tumors; therefore, PD-L1 status might be considered a new biomarker that deserves upfront testing. New combinations of immune checkpoint inhibitors and with chemotherapy have been tested in first-line treatment. However, some questions remain unanswered such as the best treatment strategy or the real upfront efficacy of these therapeutic strategies in the whole lung cancer population. In this review we summarize the main results in the first-line setting of recent phase III trials with immune checkpoint inhibitors in advanced non-small cell lung cancer patients.

Malignant pleural mesothelioma (MPM) frequently express elevated AKT/mTOR activity. Previous reports in gliomas, colon, breast and prostate cancer suggest that PTEN/PI3K pathway may be important for the induction of PD-L1 expression. This study explored the expression of PTEN/PI3K pathway and PD-L1 in MPM and its relationship with the patient́s prognosisTwenty seven consecutive MPM patients were reviewed. Formalin-fixed, paraffin-embedded tissue biopsies were used for immunohistochemical analysis of PTEN/PI3K pathway and PD-L1 RESULTS: Expression of PTEN, mTOR, pAKT, p4EBP1, peif4E, pS6 and FOXO3a was found in 88.5%, 92.3%, 78.3%, 38.5%, 100%, 52.2% and 100% of tumors and PD-L1 in 23%. We found a significant correlation between pAKT, FOXO3a and PD-L1 expression and longer overall survival (p 0.05). We did not identify significant association between the level of PD-L1 expression and alterations in PI3K pathwayThis study shows PTEN/PI3K pathway and PD-L1 in MPM are frequently activated. Our results suggests that there is not association between PD-L1 and the involvement of the PI3K pathway in MPM.

Background WNT pathway mutations (mut) are uncommon in NSCLC. Recent preclinical studies suggest that APC/CTNNB1 mut induce immune resistance in lung adenocarcinoma but how they may impact on immunotherapy response in the clinics remains unclear. Objective: our aim is to describe the clinical outcomes - Overall survival (OS) and progression-free-survival (PFS) and response rate (RR) - of a metastatic NSCLC cohort with APC/CTNNB1 mut treated with immunotherapy. Methods We selected those patients with metastatic NSCLC and APC or CTNNB1 mut detected through Amplicon-Seq (tissue), Foundation (plasma), Guardant (plasma) or exome sequencing (tissue) performed from 2014 to 2018. Results Incidence of APC/CTNNB1 mut in NSCLC in our hospital has been 1,26% and 0,7% respectively by Amplicon-Seq (tissue) and 10.4% and 1.04% respectively by exome sequencing (tissue). We identified 27 patients with APC (81%) or CTNNB1 (19%) mutations. The median age of the patients was 59 years (44-74), 72% of them were male and most frequent histology was adenocarcinoma (66%). Fifteen of the patients received ICI, 27% as a first line treatment and 47% as a second line. Interestingly, 1 patient had EGFR mut (exon 19 and 20) and 4 patients had KRAS mut. Median OS of the whole cohort from date of diagnosis was 24.5 months (CI95% 13.7-NA). Median OS was 23.5 months (CI95% 10.4-NA) for those patients who harboured CTNNB1 mut and 57.3 months (CI95% 13.7-NA) for those patients with APC mut (HR 1.8, CI95% 0.32-10, p = 0.5). Median PFS with ICI was 6.6 months (CI95% 0.9-NA). Median PFS was 0.7 months (CI95% 0.5-NA) for those patients with CTNNB1 mut and 8.9 months (CI95% 1.8-NA) with APC mut (HR 6.7, CI95% 1.1-41, p = 0.04). None of the 2 CTNNB1 mut patients responded to ICI, while RR in the APC mut cohort was 30% (4 out of 13). Conclusions In our cohort, APC mut did not show to impair clinical outcomes. Few CTNNB1 mut cases hinder conclusive analyses. Correlation with other predictive biomarkers such as tumor mutation burden and PDL1 expression is ongoing. Legal entity responsible for the study Vall d´Hebron Institute of Oncology (VHIO). Funding Grant from: Carlos III Institute of Health, Madrid, Spain: PI14/01248 and PI17/00938. Disclosure P. Iranzo: Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Rovi; Advisory / Consultancy: Kyowa Kirin; Advisory / Consultancy, Travel / Accommodation / Expenses: Grunental. A. Callejo: Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Kyowa kirin; Travel / Accommodation / Expenses: Celgene. N. Pardo: Advisory / Consultancy: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Boehringer. A. Martinez: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer. A. Navarro: Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer; Advisory / Consultancy: Oryzon Genomics; Travel / Accommodation / Expenses: MSD. S. Cedres: Advisory / Consultancy: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer ; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer; Advisory / Consultancy: MSD; Advisory / Consultancy: Amphera. R. Dienstmann: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Symphogen; Speaker Bureau / Expert testimony: Ipsen; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Servier; Research grant / Funding (institution): Merck. H.G. Palmer: Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Blueprint; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Cellestia. A. Vivancos: Advisory / Consultancy, Research grant / Funding (institution): SYSMEX; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: MERCK; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Guardant Health; Licensing / Royalties, Technology Transfer DX Field: Ferrer; Research grant / Funding (institution): DEBIO; Research grant / Funding (institution): Cellestia; Research grant / Funding (institution): Chittern. E. Felip: Advisory / Consultancy: Abbvie; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy: Boehringer Ingelheim,; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Janssen; Advisory / Consultancy: Medscape; Advisory / Consultancy: Merck KGaA; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: Takeda; Advisory / Consultancy: Touchtime; Research grant / Funding (institution): Fundacion Merck Salud; Research grant / Funding (institution): Grant for Oncology Innovation EMD Serono. All other authors have declared no conflicts of interest.

Resumen Se presenta una actualizacion del tratamiento del osteosarcoma convencional, con exclusion de las formas secundarias por malignizacion de otras patologias, asi como las formas de osteosarcoma parostal-yuxtacortical. La supervivencia global es del 73%, aunque el protocolo sigue abierto y se evalua la toxicidad y se plantean cambios en la forma de administrar las drogas para disminuir los efectos secundarios a corto y largo plazo.

An update on the conventional treatment of osteosarcoma, excluding secondary forms due to malignancies by other diseases, as well as the parosteal-juxtacortical forms. The overall survival is 73%, although the protocol is still open. The toxicity and changes established in the forms of administering the drugs to decrease the secondary effects in the short and long term are assessed.

La histiocitosis de células de Langerhans (HCL), anteriormente conocida como histiocitosis X, es una enfermedad poco frecuente caracterizada por la acumulación y proliferación de histiocitos, eosinófilos y células de Langerhans, con inclusión de gránulos de Birbeck detectables por microscopia electrónica, afectando órganos y sistemas de forma aislada o múltiple. Las distintas formas de presentación producen distinto enfoque terapéutico y pronóstico, desde formas benignas, autolimitadas, con resolución espontánea hasta otras de curso tórpido o maligno. Se presentan 5 casos de HCL exponentes de esta entidad, con la misma base histopatológica, pero diferente evolución. : Langerhans' cell histiocytosis (LCH), previously known as histiocytosis X, is a rare disease. It is characterized by the accumulation and proliferation of histiocytes, eosinophils and Langerhans' cells with Birbeck granules detected by electron microscopy. It involves single organs or systems or can present as a multisystem disease. The clinical presentation may vary widely, ranging from benign self-limiting types with spontaneous regression to slowlyprogressive malignant disease. We report five cases of LCH with the same histopathologic basis but different outcome.

Background Study results demonstrated that IFN augments BEV activity and improves median PFS in pts with mRCC. Thus, combination BEV + IFN is a standard first-line treatment option for mRCC. Combining BEV with the mTOR inhibitor EVE may be an efficacious and well-tolerated treatment option. The open-label, phase II RECORD-2 trial compared first-line EVE + BEV and IFN + BEV in mRCC. Patients and methods: Therapy-naive pts with clear cell mRCC and prior nephrectomy were randomized 1:1 to BEV 10 mg/kg IV every 2 weeks with either EVE 10 mg oral daily or IFN (9 MIU SC 3 times/week, if tolerated). Tumour assessments were every 12 weeks. Primary objective was treatment effect on progression-free survival (PFS) per central review based on an estimate of the chance of a subsequent phase III trial success (50% threshold for phase II success). Results In EVE + BEV (n = 182) and IFN + BEV (n = 183) arms, median age was 60/60 years, 76/72% of pts were men, MSKCC risk was favourable/intermediate/poor in 36/57/7% and 36/57/7% of pts, and 43/46% of pts had >2 organs involved, respectively. For EVE + BEV and IFN + BEV, median treatment duration was 8.5/8.3 months, respectively; 23/26% of pts discontinued due to AEs. In EVE + BEV and IFN + BEV arms, median PFS by central review was 9.3/10.0 months (HRIFN/EVE, 0.91; 95% CI, 0.69-1.19; P =0.485), respectively; probability of subsequent phase III success was 5.1%. Results of central and local PFS analysis were consistent. Objective response rate was 27/28% in EVE + BEV and IFN + BEV arms, respectively. Median overall survival (OS) was not reached in the EVE + BEV arm and was 25.9 months (95% CI: 21.1, 30.2) in the IFN + BEV arm. Most frequent AEs (%) were stomatitis (63), proteinuria (49), diarrhoea (39), hypertension (38), and epistaxis (35) in EVE + BEV arm and decreased appetite (45), fatigue (41), proteinuria (37), and pyrexia (35) in IFN + BEV arm. Conclusions In RECORD-2, PFS and tolerability were similar for first-line EVE + BEV and IFN + BEV. Final OS analysis will occur after 2-year follow-up. Disclosure A. Ravaud: Alain Ravaud is a member of global, European, and/or French boards on urological tumors for Pfizer, Novartis, GlaxoSmithKline, Bayer-Schering, and Dendreon, and has received institutional grant support from Pfizer, Novartis, and Roche. O. Anak: Ozlem Anak is an employee of Novartis Pharma AG. D. Pelov: Diana Pelov is an employee of Novartis Pharmaceuticals Corporation. A. Louveau: Anne-Laure Louveau is an employee of Novartis Pharma S.A.S. T. M-H: Tay M-H is a speaker for an advisory board for Novartis Pharmaceuticals Corporation. B. Melichar: Bohuslav Melichar has received honoraria from Novartis and Roche and served on an advisory board for Roche. All other authors have declared no conflicts of interest.

Background Response to neoadjuvant chemotherapy has been associated with an improvement in survival in MIBC. The analysis of genetic markers involved in DNA repair pathways could be useful to predict chemosensitivity to cisplatin-based regimens. BRCA1 plays a central role in DNA repair and cell-cycle checkpoint control. However, BRCA1 function can be modulated by other DNA repair genes. RAP80 acts upstream of BRCA1 and regulates BRCA1 function after DNA damage. AEG-1 can induce BRCA1 expression and cause chemoresistance by activating PI3K/Akt and NF-KB pathways. Methods Paraffin-embedded pre-treatment tumor samples were collected by transurethral resection from 65 p with resectable MIBC stage T2-4N0M0 treated with neoadjuvant cisplatin-based chemotherapy. Gene expression levels of BRCA1, RAP80 and AEG-1 were quantified by real-time quantitative PCR. Expression levels were divided into terciles and correlated with median survival (MS). Results 33 p were treated with cisplatin, methotrexate and vinblastine (CMV) and 32 p with cisplatin and gemcitabine. Chemotherapy was followed by cystectomy in 60 p. Overall MS was not reached and 5-year survival was 51%. 16 p (38%) with low/intermediate BRCA1 levels had a complete pathological response (pR), while only 1 p (5%) with high BRCA1 levels had a complete pR (P = 0.006). MS was 45 months (m) and 5-year survival was 27% in 21 p with high BRCA1 mRNA levels vs 168 m and 59% in 44 p with low/intermediate levels (P = 0.05). No differences in MS were observed according to RAP80 mRNA levels. MS was 50 m in 15 p with high AEG-1 levels, 45 m in 15 p with intermediate levels, and was not reached in 18 p with low levels, although these differences were not statistically significant (P = 0.3). Conclusions Low/intermediate BRCA1 mRNA expression is associated with better pR and longer MS and 5-year survival to cisplatin-based neoadjuvant chemotherapy in p with MIBC. BRCA1 levels can be useful in customizing chemotherapy in these p. Further studies with larger numbers of p are warranted to elucidate the role of other molecular markers, including AEG-1, in this setting. Disclosure All authors have declared no conflicts of interest.

Introduction Although neoadjuvant chemotherapy is a recommended treatment in MIBC, it has not gained widespread acceptance in clinical practice, due to the lack of predictive markers of efficacy and the absence of a standard chemotherapy regimen. Furthermore, since few studies have assessed the role of neoadjuvant chemotherapy in an off-protocol setting, there may be doubts about its feasibility. Material and methods We retrospectively analyzed 124 p with MIBC treated with neoadjuvant cisplatin-based chemotherapy at two centers from 1991 to 2010. Clinical and pathological variables were correlated with survival. All patients were classified as stage cT2-4N0M0 based on TUR (trans-urethral resection) and CT scan findings and were candidates for neoadjuvant chemotherapy followed by cystectomy. Results 10 p (8%) were cT2N0, 83 p (66%) cT3N0, and 31 p (26%) cT4aN0. 60 p (48%) were treated with CMV (cisplatin, methotrexate and vinblastine) and 64 p (52%) with cisplatin/gemcitabine (CG). One patient died from treatment-related toxicity. A complete resection was performed in 109 p (87%). A significant pathological response (pR) (pT0-1) was obtained in 60 p (48%). Median survival (MS) and 5-year (5y) survival were 59 months (m) and 50%, respectively. Median cancer-specific survival (CSS) was not reached and 5y CSS was 64%. 5y overall survival was similar (50.3% vs 50.9%) in p treated with CMV or CG. In p with a significant pR, 5y survival was 77%, while for p who did not respond to chemotherapy (pT3-4NO or N+), it was 8.3%. Only complete resection (HR:3.36, P = 0.006) and lymphovascular invasion (LVI) (HR:17.29, P Conclusions Neoadjuvant chemotherapy followed by cystectomy is feasible in p with locally-advanced MIBC. Both CMV and CG are active regimens, with 5-y survival that compares favorably with surgery alone. p responding to neoadjuvant chemotherapy have an excellent prognosis, while those who do not respond should be considered for non-cross-resistant adjuvant chemotherapy. Disclosure All authors have declared no conflicts of interest.

Introducción: El desarrollo de inhibidores frente al factor VIII en la hemofilia constituye una grave complicación. Se observa en el 20-30 % de los pacientes con hemofilia moderada y grave. El tratamiento más empleado es la inducción de inmunotolerancia con administración diaria de altas dosis de factor VIII. El 25-35% de los pacientes no responden, presentando hemartrosis frecuentes y riesgo de hemorragia vital. Otra alternativa terapéutica es la inmunosupresión. Recientemente se han empleado con éxito nuevos fármacos en el tratamiento de enfermedades autoinmunes refractarias al tratamiento convencional, como el rituximab que es un anticuerpo monoclonal anti-CD20 dirigido contra los linfocitos B. Caso clínico: Presentamos un niño de 7 años de edad, diagnosticado a la edad de 13 meses de hemofilia A grave (nivel de FVIII < 1 UI/dl). Desarrolló un inhibidor tras la primera dosis de factor VIII recombinante con un título de 11,8 U Bethesda (UB). Inició el tratamiento de inmunotolerancia con la administración diaria de 100 UI/kg de factor VIII recombinante a través de un porth-a-cath. El reservorio se colocó con el apoyo de administración de factor VII activado. El nivel del inibidor fluctuó durante los 2 años siguientes entre 0,1 y 29,3 UB, sin clínica hemorrágica significativa. Se cambió el tratamiento sustitutivo a factor VIII humano, con disminución transitoria del inhibidor, que se mantuvo durante 4 años entre 2 y 40 UB. A los 7 años de edad y tras un aumento del inhibidor a 49,8 UB comienzan a aparecer hematomas musculares frecuentes en pantorrillas y antebrazos, que precisan tratamiento con factor VII activado recombinante. Aparte del elevado coste del tratamiento, el paciente y su familia tenían muy limitada su calidad de vida, por la dependencia hospitalaria. Se informó a la familia de la posibilidad del tratamiento con rituximab y tras obtención del consentimiento informado para su uso compasivo, se inició la administración durante 4 semanas de una dosis semanal de rituximab a 375 mg/m2/dosis. Tras la primera dosis, presentó una reacción anafiláctica consistente en prurito, disnea, taquicardia e hipotensión que cedió tras la administración de difenhidramina e hidrocortisona y disminución del ritmo de infusión de rituximab. Los niveles de inhibidor tras las 4 semanas disminuyeron a 1,2 UB y se mantuvieron en valores inferiores a 3 UB durante las 18 semanas siguientes. La cifra total de linfocitos permaneció inalterada en tanto que los linfocitos B fueron indetectables durante este tiempo. Las concentraciones de inmunoglobulinas G, A y M disminuyeron ligeramente, pero permaneciendo en límites normales. No se observó aumento del número de infecciones. La profilaxis con factor VIII se redujo desde 200 UI/kg/ día hasta 50 UI/kg, tres veces por semana. Tras observar un aumento de los linfocitos B, se observó un incremento del inhibidor a 34,4 UB con reaparición de clínica hemorrágica. Se repitió la tanda semanal de rituximab durante 4 semanas, continuando con una administración mensual y espaciando posteriormente el intervalo de administración hasta llegar a cada 12 semanas, con monitorización del nivel de inhibidor. El paciente está libre de clínica hemorrágica y no se ha observado reaparición del inhibidor, siguiendo el tratamiento con administración de una dosis única de rituximab cada 12 semanas. Conclusión: Según nuestra experiencia, el tratamiento con rituximab puede ser eficaz en el tratamiento de inhibidores en la hemofilia grave y tras la dosis inicial, debe ser mantenido con la mínima dosis necesaria para la obtención de la respuesta clínico-biológica deseada.

Diethyl allylmalonates or 2-arylalkanoic esters are prepared in good yield by reductive α-deoxygenation of the corresponding α-acetoxy or α-alkony esters. Since the intermediate ester enolates are generated under aprotic conditions, a one pot reductive-alkylation is also possible. One application of this procedure allows diethyl oxomalonate to serve as a conjunctive reagent for stitching together an alkene and an alkyl halide with a malonyl group as linchpin.