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- Administração subcutânea de bortezomib: evolução no tratamento do mieloma múltiplo: a experiência do HFFPublication . Santos, R; Gomes, FIntrodução: O Mieloma Múltiplo representa 1% das neoplasias malignas humanas. Na última década as novas terapêu- ticas tiveram relevante impacto no aumento da sobrevivência. O bortezomib constitui uma das novas opções de tratamento, no entanto as neuropatias constituem as toxicidades limitantes de dose e podem impedir a optimização dos resultados. A administração subcutânea (SC) de bortezomib, foi aprovada pela European Medicines Agency (EMA) em Setembro de 2012 e constitui uma das estratégias para reduzir a incidência de neuropatias (NP) em relação à administração endovenosa tradi- cional. É usado no Hospital Fernando Fonseca (HFF) desde Fevereiro de 2012 após aprovação institucional. Material e Métodos: Estudo retrospectivo comparativo, unicêntrico, após revisão do processo clínico de 43 doentes, 28 tratados com bortezomib endovenoso (EV) e 21 com bortezomib SC, em 6 comutou-se para bortezomib SC. Administradas 497 inoculações. A administração foi protocolada: técnica de preparação do inóculo, modo de administração, registo indi- vidualizado, monitorização e intervenção precoce em reacções acessórias (RA). Avaliou-se a segurança: RA em relação com técnica de administração e RA sistémicas associadas a toxicidade aguda ou cumulativa. Resultados: Análise de segurança em 497 inoculações de bortezomib SC, realizadas em 21 doentes em 18 meses consecu- tivos. Feita análise comparada com o histórico para o bortezomib EV. Identificadas como RA locais rash máculo-eritematoso no local do inóculo, com regressão em 95% dos casos até às 72h, em nenhum caso associado a sintomas constitucionais. Em relação à ocorrência de neuropatias para bortezomib SC versus (vs) EV, constatou-se ausência de NP em 80% vs 19%, NP sensitiva grau 1-2 em 19 vs 62%, NP motora em 0 vs 12%, NP autonómica em 9,5% vs 18%. Ocorreu redução de dose e sus- pensão em 12 e 31% vs 0 e 0% respectivamente para bortezomib SC e bortezomib EV. Conclusões: O bortezomib SC preserva a eficácia com redução da incidência e gravidade das neuropatias limitantes de dose e boa tolerabilidade local. Não ocorreu suspensão por motivos iatrogénicos. A preparação e inoculação é exequível a partir da formulação parentérica EV, permitindo atingir doses cumulativas superiores, optimizando a eficácia e constituindo uma opção válida na gestão das neuropatias limitantes de dose.
 - Associação entre anemia perniciosa e tumor carcinóide gástrico: a propósito de um caso clínicoPublication . Carvalho, R; Leichsenring, C; Félix, J; Gomes, F; Manso, RT; Geraldes, V; Cuña, L; Branquinho, F; Perloiro, MCOs tumores carcinóides gástricos são raros, representando ≤ 1% dos tumores gástricos e 8,7% de todos os carcinóides gastrentestinais. Os autores descrevem o caso clínico de uma mulher de 32 anos admitida por anemia macrocítica, e cuja investigação etiológica revelou tratar-se de uma anemia perniciosa (AP). Realizou uma endoscopia digestiva alta (EDA), onde se encontraram 6 nódulos bem delimitados no corpo e fundo gástricos. O resultado histopatológico foi consistente com o diagnóstico de tumor carcinóide, bem diferenciado. Após exclusão de metastização secundária (por TC e cintigrafia com octreótido), tendo em conta o envolvimento multifocal do tumor e a presença de metaplasia intestinal completa no corpo e fundo gástricos, a doente foi proposta para gastrectomia total que decorreu sem intercorrências. Iniciou terapêutica com vitamina B-12, com excelente resposta clínica e analítica. O objectivo da publicação deste caso assenta no alertar para o risco do aparecimento dos carcinóides gástricos nos doentes com AP e da necessidade de realização de EDA imediatamente após o diagnóstico da mesma. Nos carcinóides gástricos tipo I que não apresentam doença à distância, a evolução é benigna.
 - Case Report: Pure Red Cell Aplasia due to Angioimmunoblastic T-Cell Lymphoma.Publication . Vitorino, M; Nunes, F; Costa, M; Porteiro, B; Borges, A; Machado, JPure red cell aplasia (PRCA) is a rare bone marrow failure characterized by a progressive normocytic anemia and reticulocytopenia without leukopenia and thrombocytopenia. It can be associated with various hematological disorders but exceedingly rarely with angioimmunoblastic T-cell lymphoma (AITL). We report the case of a 72-year-old woman with PRCA associated with AITL. The patient presented with severe anemia (hemoglobin 2.6 g/dL) and a low reticulocyte count 0.7%. Direct and indirect Coombs tests were positive. A CT scan of the chest, abdomen, and pelvis revealed multiple lymphadenopathies. A cervical lymph node biopsy was compatible with AITL. A bone marrow biopsy showed medullary involvement by AITL and a severe erythroid hypoplasia with a myeloid:erythroid ratio of 19.70. The patient was started on CHOP and after 6 cycles the PET scan confirmed complete remission
 - Conversion to resection of liver metastases from colorectal cancer with hepatic artery infusion of combined chemotherapy and systemic cetuximab in multicenter trial OPTILIV.Publication . Lévi, FA; Boige, V; Hebbar, M; Smith, D; Lepère, C; Focan, C; Karaboué, A; Guimbaud, R; Carvalho, C; Tumolo, S; Innominato, P; Ajavon, Y; Truant, S; Castaing, D; De Baere, T; Kunstlinger, F; Bouchahda, M; Afshar, M; Rougier, P; Adam, R; Ducreux, M; Association Internationale pour Recherche sur Temps Biologique et Chronothérapie (ARTBC International)BACKGROUND: Systemic chemotherapy typically converts previously unresectable liver metastases (LM) from colorectal cancer to curative intent resection in ∼15% of patients. This European multicenter phase II trial tested whether hepatic artery infusion (HAI) with triplet chemotherapy and systemic cetuximab could increase this rate to 30% in previously treated patients. PATIENTS AND METHODS: Participants had unresectable LM from wt KRAS colorectal cancer. Main non-inclusion criteria were advanced extra hepatic disease, prior HAI and grade 3 neuropathy. Irinotecan (180 mg/m(2)), oxaliplatin (85 mg/m(2)) and 5-fluorouracil (2800 mg/m(2)) were delivered via an implanted HAI access port and combined with i.v. cetuximab (500 mg/m(2)) every 14 days. Multidisciplinary decisions to resect LM were taken after every three courses. The rate of macroscopic complete resections (R0 + R1) of LM, progression-free survival (PFS) and overall survival (OS) were computed according to intent to treat. RESULTS: The patient population consisted of 42 men and 22 women, aged 33-76 years, with a median of 10 LM involving a median of six segments. Up to 3 extrahepatic lesions of <1 cm were found in 41% of the patients. A median of six courses was delivered. The primary end point was met, with R0-R1 hepatectomy for 19 of the 64 previously treated patients, 29.7% (95% confidence interval 18.5-40.9). Grade 3-4 neutropenia (42.6%), abdominal pain (26.2%), fatigue (18%) and diarrhea (16.4%) were frequent. Objective response rate was 40.6% (28.6-52.3). Median PFS and OS reached 9.3 (7.8-10.9) and 25.5 months (18.8-32.1) respectively. Those with R0-R1 hepatectomy had a median OS of 35.2 months (32.6-37.8), with 37.4% (23.6-51.2) alive at 4 years. CONCLUSION: The coordination of liver-specific intensive chemotherapy and surgery had a high curative intent potential that deserves upfront randomized testing.
 - Coriocarcinoma não gestacional. Origem extragonadal? Caso clínicoPublication . Carvalho, R; Gomes, F; Gonçalves, L; Miranda, S; Branquinho, F; Dutschmann, LOs germinomas têm habitual localização gonadal, raramente ocorrendo de forma isolada em locais extragonadais da linha média e cujo comportamento biológico é similar aos primeiros, apesar do prognóstico ser mais desfavorável. O diagnóstico de coriocarcinoma não gestacional extragonadal é uma entidade rara, só podendo ser definido após a exclusão de patologia gonadal. Os autores descrevem o caso de um homem de 31 anos, com manifestação adenopática abdominal e lesões ocupando espaço no fígado. A biopsia cirúrgica revelou tratar-se de um coriocarcinoma puro e cujo inventário de extensão de doença revelou ser TxN3M1bS2. A urgência da situação implicou tratamento imediato com esquema de quimioterapia BEP (bleomicina, etoposido e cisplatina), com resposta completa clínico-laboratorial. Posteriormente, procedeu-se a orquidectomia radical à esquerda, orientada por alterações ecográficas, cuja avaliação anátomopatológica não identificou tecido neoplásico viável. O doente encontra-se em remissão completa com um follow-up de 24 meses pós-terapêutica.
 - Decreased Survival in African Patients with Triple Negative Breast CancerPublication . Honório, M; Guerra-Pereira, N; Silva, J; Alves, J; Filipa, A; Braga, SAbstract Introduction: Triple Negative Breast Carcinomas (TNBC) are more prevalent in younger women especially those with African Ancestry, in whom the disease appears to be more aggressive. Since there are no data on Africans living in continental Europe, we sought to analyse a sample of African women from a European country and determine if, like African Americans, they have more aggressive tumor biology and poorer outcomes. Methods: We performed a retrospective review of TNBC to compare clinical and pathological features and survival between African and non-African patients. All women presented with breast cancer (BC), between 2005 and 2014, to a single general hospital, in Portugal. Results: A total of 144 (9.3% of the whole sample) TNBC patients were identified and amongst these, 17 were African (12%). African patients were not significantly younger than non-African patients (median age of 60 years vs 57.2 years, respectively, p=0.59). Regarding tumor size, nodal status and histologic grade at presentation, these variables were very similar between the two cohorts. Nevertheless, the prevalence of initially metastatic BC was significantly higher among the African population (41.2% vs 11%, p<0,005) and the outcome was worse for these patients (median survival: 62 vs 15 months, p<0.005). Conclusions: Our study demonstrated that African patients more frequently presented with late stage disease and worse survival outcome than the non-African population. These findings may be explained by more aggressive tumor biology.
 - Early tumour response as a survival predictor in previously- treated patients receiving triplet hepatic artery infusion and intravenous cetuximab for unresectable liver metastases from wild-type KRAS colorectal cancer.Publication . Bouchahda, M; Boige, V; Smith, D; Karaboué, A; Ducreux, M; Hebbar, M; Lepére, C; Focan, C; Guimbaud, R; Innominato, P; Awad, S; Carvalho, C; Tumolo, S, et al.BACKGROUND: Surgery for colorectal liver metastases results in an overall survival of about 40% at 5 years. Progression-free survival is increased with the addition of oxaliplatin and fluorouracil chemotherapy. The addition of cetuximab to these chemotherapy regimens results in an overall survival advantage in patients with advanced disease who have the KRAS exon 2 wild-type tumour genotype. We aimed to assess the benefit of addition of cetuximab to standard chemotherapy in patients with resectable colorectal liver metastasis. METHODS: Patients with KRAS exon 2 wild-type resectable or suboptimally resectable colorectal liver metastases were randomised in a 1:1 ratio to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done using minimisation with factors of surgical centre, poor prognostic tumour (one or more of: ≥ 4 metastases, N2 disease, or poor differentiation of primary tumour), and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m(2) intravenously over 2 h and fluorouracil bolus 400 mg/m(2) intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m(2) repeated every 2 weeks (regimen one) or oxaliplatin 130 mg/m(2) intravenously over 2 h and oral capecitabine 1000 mg/m(2) twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m(2) intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given as an intravenous dose of 500 mg/m(2) every 2 weeks with regimen one and three or a loading dose of 400 mg/m(2) followed by a weekly infusion of 250 mg/m(2) with regimen two. The primary endpoint was progression-free survival. This is an interim analysis, up to Nov 1, 2012, when the trial was closed, having met protocol-defined futility criteria. This trial is registered, ISRCTN22944367. FINDINGS: 128 KRAS exon 2 wild-type patients were randomised to chemotherapy alone and 129 to chemotherapy with cetuximab between Feb 26, 2007, and Nov 1, 2012. 117 patients in the chemotherapy alone group and 119 in the chemotherapy plus cetuximab group were included in the primary analysis. The median follow-up was 21.1 months (95% CI 12.6-33.8) in the chemotherapy alone group and 19.8 months (12.2-28.7) in the chemotherapy plus cetuximab group. With an overall median follow-up of 20.7 months (95% CI 17.9-25.6) and 123 (58%) of 212 required events observed, progression-free survival was significantly shorter in the chemotherapy plus cetuximab group than in the chemotherapy alone group (14.1 months [95% CI 11.8-15.9] vs 20.5 months [95% CI 16.8-26.7], hazard ratio 1.48, 95% CI 1.04-2.12, p=0.030). The most common grade 3 or 4 adverse events were low neutrophil count (15 [11%] preoperatively in the chemotherapy alone group vs six [4%] in the chemotherapy plus cetuximab group; four [4%] vs eight [8%] postoperatively), embolic events (six [4%] vs eight [6%] preoperatively; two [2%] vs three [3%] postoperatively), peripheral neuropathy (six [4%] vs one [1%] preoperatively; two [2%] vs four [4%] postoperatively), nausea or vomiting (four [3%] vs six [4%] preoperatively; four [4%] vs two [2%] postoperatively), and skin rash (two [1%] vs 21 [15%] preoperatively; 0 vs eight [8%] postoperatively). There were three deaths in the chemotherapy plus cetuximab group (one interstitial lung disease and pulmonary embolism, one bronchopneumonia, and one pulmonary embolism) and one in the chemotherapy alone group (heart failure) that might have been treatment related. INTERPRETATION: Addition of cetuximab to chemotherapy and surgery for operable colorectal liver metastases in KRAS exon 2 wild-type patients results in shorter progression-free survival. Translational investigations to explore the molecular basis for this unexpected interaction are needed but at present the use of cetuximab in this setting cannot be recommended.
 - ERF3A/GSPT1 12-GGC allele increases the susceptibility for breast cancer developmentPublication . Malta-Vacas, J; Chauvin, C; Gonçalves, L; Nazaré, A; Carvalho, C; Monteiro, C; Bagrel, D; Jean-Jean, O; Brito, M
 - Esclerose tuberosa: doença genética raraPublication . Atalaia, G; Vasconcelos, P; Bragança, N
 - Fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancerPublication . Innominato, PF; Giacchetti, S; Moreau, T; Bjarnason, GA; Smaaland, R; Focan, C; Garufi, C; Iacobelli, S; Tampellini, M; Tumolo, S; Carvalho, C; Karaboué, A; Poncet, A; Spiegel, D; Lévi, F; International Association for Research on Time in Biology and Chronotherapy (ARTBC) Chronotherapy Group.BACKGROUND:Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the early occurrence of chemotherapy-induced symptoms correlated with circadian disruption would selectively hinder the efficacy of chronotherapy. METHODS:Fatigue and weight loss (FWL) were considered to be associated with circadian disruption based on previous data. Patients with metastatic colorectal cancer (n = 543) from an international phase 3 trial comparing FOLFOX2 with chronoFLO4 were categorized into 4 subgroups according to the occurrence of FWL or other clinically relevant toxicities during the initial 2 courses of chemotherapy. Multivariate Cox models were used to assess the role of toxicity on the time to progression (TTP) and overall survival (OS). RESULTS:The proportions of patients in the 4 subgroups were comparable in both treatment arms (P = .77). No toxicity was associated with TTP or OS on FOLFOX2. The median OS on FOLFOX2 ranged from 16.4 (95% confidence limits [CL], 7.2-25.6 months) to 19.8 months (95% CL, 17.7-22.0 months) according to toxicity subgroup (P = .45). Conversely, FWL, but no other toxicity, independently predicted for significantly shorter TTP (P < .0001) and OS (P = .001) on chronoFLO4. The median OS on chronoFLO4 was 13.8 months (95% CL, 10.4-17.2 months) or 21.1 months (95% CL, 19.0-23.1 months) according to presence or absence of chemotherapy-induced FWL, respectively. CONCLUSIONS: Early onset chemotherapy-induced FWL was an independent predictor of poor TTP and OS only on chronotherapy. Dynamic monitoring to detect early chemotherapy-induced circadian disruption could allow the optimization of rapid chronotherapy and concomitant improvements in safety and efficacy.
 
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