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BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling. METHODS: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis. RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group. CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Carbamatos/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Progressão da Doença , Eletrocorticografia , Feminino , Humanos , Análise de Intenção de Tratamento , Irinotecano/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
Aim: Pleural dissemination of pseudomyxoma peritonei (PMP) is an extremely rare diagnosis, for which no standard therapy is available.Methods: We describe the successful treatment of a 67-year-old male diagnosed with left-sided intrapleural dissemination of PMP (low-grade appendiceal mucinous neoplasm), 2 years after treatment of abdominal PMP with cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy. Treatment consisted of extended pleural decortication (ePD) and oxaliplatin-based hyperthermic intrathoracic chemotherapy (HITHOC). The patient is doing well without complications or signs of recurrence, 26 months after thoracic surgery.Conclusion: ePD in combination with HITHOC is a valuable treatment for thoracic PMP.
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Neoplasias do Apêndice , Hipertermia Induzida , Neoplasias Peritoneais , Pseudomixoma Peritoneal , Idoso , Neoplasias do Apêndice/terapia , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , Humanos , Masculino , Neoplasias Peritoneais/diagnóstico por imagem , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/cirurgia , Pseudomixoma Peritoneal/diagnóstico por imagem , Pseudomixoma Peritoneal/tratamento farmacológico , Pseudomixoma Peritoneal/cirurgia , Estudos RetrospectivosRESUMO
Background Overcoming resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) in patients with KRAS wildtype (WT) metastatic colorectal cancer (mCRC) could help meet the needs of patients with limited treatment options. Methods In this phase 1b study, patients with N/KRAS WT, MET-positive mCRC who had progressed following anti-EGFR mAb treatment received escalating oral doses of capmatinib (150, 300, and 400 mg) twice daily plus weekly intravenous cetuximab (at the approved dose). The primary objective was to establish a recommended dose for expansion (RDE) of capmatinib in combination with cetuximab. Safety, preliminary activity, pharmacokinetics, and pharmacodynamics were also explored. Results Thirteen patients were enrolled. No patients experienced a dose-limiting toxicity at investigated doses; the RDE was established as capmatinib 400 mg twice daily plus cetuximab. All patients experienced adverse events (AEs) suspected to be related to the study treatment. Five patients (38.5%) reported study-drug-related AEs of grade 3/4 in severity. No patients achieved a complete or partial response according to RECIST v1.1; however, tumor shrinkage of 29-44% was observed in 4 patients. Conclusions Capmatinib plus cetuximab was well tolerated. Preliminary signs of activity were observed. Further investigation is warranted to obtain efficacy data and refine predictive biomarkers of response. Clinical trial registration NCT02205398.
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Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzamidas/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Imidazóis/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Triazinas/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Linhagem Celular Tumoral , Cetuximab/efeitos adversos , Cetuximab/farmacocinética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-met/metabolismo , Critérios de Avaliação de Resposta em Tumores Sólidos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Triazinas/efeitos adversos , Triazinas/farmacocinética , Proteínas ras/genéticaRESUMO
PURPOSE: The widespread use of gallium-68-labelled somatostatin analogue (SSA) PET, the current standard for somatostatin receptor (SSTR) imaging, is limited by practical and economic challenges that could be overcome by a fluorine-18-labelled alternative, such as the recently introduced [18F]AlF-NOTA-octreotide ([18F]AlF-OC). This prospective trial aimed to evaluate safety, dosimetry, biodistribution, pharmacokinetics and lesion targeting of [18F]AlF-OC and perform the first comparison with [68Ga]Ga-DOTATATE in neuroendocrine tumour (NET) patients. METHODS: Six healthy volunteers and six NET patients with a previous clinical [68Ga]Ga-DOTATATE PET were injected with an IV bolus of 4 MBq/kg [18F]AlF-OC. Healthy volunteers underwent serial whole-body PET scans from time of tracer injection up to 90 min post-injection, with an additional PET/CT at 150 and 300 min post-injection. In patients, a 45-min dynamic PET was acquired and three whole-body PET scans at 60, 90 and 180 min post-injection. Absorbed organ doses and effective doses were calculated using OLINDA/EXM. Normal organ uptake (SUVmean) and tumour lesion uptake (SUVmax and tumour-to-background ratio (TBR)) were measured. A lesion-by-lesion analysis was performed and the detection ratio (DR), defined as the fraction of detected lesions was determined for each tracer. RESULTS: [18F]AlF-OC administration was safe and well tolerated. The highest dose was received by the spleen (0.159 ± 0.062 mGy/MBq), followed by the urinary bladder wall (0.135 ± 0.046 mGy/mBq) and the kidneys (0.070 ± 0.018 mGy/MBq), in accordance with the expected SSTR-specific uptake in the spleen and renal excretion of the tracer. The effective dose was 22.4 ± 4.4 µSv/MBq. The physiologic uptake pattern of [18F]AlF-OC was comparable to [68Ga]Ga-DOTATATE. Mean tumour SUVmax was lower for [18F]AlF-OC (12.3 ± 6.5 at 2 h post-injection vs. 18.3 ± 9.5; p = 0.03). However, no significant differences were found in TBR (9.8 ± 6.7 at 2 h post-injection vs. 13.6 ± 11.8; p = 0.35). DR was high and comparable for both tracers (86.0% for [68Ga]Ga-DOTATATE vs. 90.1% for [18F]AlF-OC at 2 h post-injection; p = 0.68). CONCLUSION: [18F]AlF-OC shows favourable kinetic and imaging characteristics in patients that warrant further head-to-head comparison to validate [18F]AlF-OC as a fluorine-18-labelled alternative for gallium-68-labelled SSA clinical PET. TRIAL REGISTRATION: Clinicaltrials.gov : NCT03883776, EudraCT: 2018-002827-40.
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Tumores Neuroendócrinos , Octreotida , Radioisótopos de Gálio , Compostos Heterocíclicos com 1 Anel , Humanos , Tumores Neuroendócrinos/diagnóstico por imagem , Octreotida/efeitos adversos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Estudos Prospectivos , Distribuição TecidualRESUMO
Background: Peptide receptor radionuclide therapy (PRRT) is a validated treatment for somatostatin receptor overexpressing neuroendocrine tumors (NETs). The NETTER-1 trial demonstrated a pronounced positive effect on progression-free-survival compared to high dose somatostatin analogs (SSAs), with a strong tendency toward overall survival benefit. Our aim was to investigate the influence of pretreatment with everolimus and/or sunitinib on subacute hematotoxicity of PRRT. To assess the influence of prior treatment with everolimus/sunitinib might be of clinical relevance due to the link between short-term hematotoxicity and increased incidence of late hematotoxicity.Material and methods: Our single-center retrospective study enrolled all patients treated with 177Lu-DOTATATE PRRT (1-4 cycles of 7.4 GBq), between November 2013 and July 2018. Patients were assigned to two groups according to their pretreatment: no targeted agents (N = 41), or targeted agents (everolimus, sunitinib or both; N = 41). The end point was subacute hematotoxicity, defined as the nadir value between the first administration until 3 months after the last administration, using the CTCAE 4.03 classification. The impact of splenectomy was also explored.Results: Eighty percent of patients had a primary gastroenteropancreatic NET. No statistically significant differences in severe subacute hematotoxicity were seen in the pretreated group vs. the naive group for hemoglobin (grade 3/4: 12% vs. 22%), neither for leucocytes (grade 3/4: 10% vs. 7%), neutrophils (grade 3/4: 5% vs. 7%), lymphocytes (grade 3/4: 49% vs. 37%) and platelets (grade 3/4: 15% vs. 15%). Furthermore, we observed significantly lower toxicity for total white blood cells, lymphocytes and platelets in the subgroup that had splenectomy (N = 12). Limitations of this study include the potential bias in lack of use of targeted agents in patients more susceptible to toxicity, and the limited number of patients and events.Conclusions: In a patient cohort with NET pretreated with everolimus and/or sunitinib, we could not demonstrate a significant effect of prior/pretreatment with everolimus and/or sunitinib on the subacute hematotoxicity of 177Lu-DOTATATE PRRT.
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Antineoplásicos/uso terapêutico , Everolimo/uso terapêutico , Doenças Hematológicas/induzido quimicamente , Neoplasias Intestinais/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Octreotida/análogos & derivados , Compostos Organometálicos/efeitos adversos , Neoplasias Pancreáticas/tratamento farmacológico , Compostos Radiofarmacêuticos/efeitos adversos , Somatostatinoma/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Sunitinibe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Feminino , Humanos , Neoplasias Intestinais/sangue , Leucopenia/induzido quimicamente , Linfopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/sangue , Octreotida/administração & dosagem , Octreotida/efeitos adversos , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/farmacocinética , Neoplasias Pancreáticas/sangue , Intervalo Livre de Progressão , Compostos Radiofarmacêuticos/administração & dosagem , Receptores de Somatostatina/metabolismo , Estudos Retrospectivos , Somatostatinoma/sangue , Somatostatinoma/mortalidade , Esplenectomia , Neoplasias Gástricas/sangue , Trombocitopenia/induzido quimicamente , Adulto JovemRESUMO
BACKGROUND: Tumour budding, described as the presence of single cells or small clusters of up to five tumour cells at the invasive margin, is established as a prognostic marker in colorectal carcinoma. In the present study, we aimed to investigate the molecular signature of tumour budding cells and the corresponding tumour bulk. METHODS: Tumour bulk and budding areas were microdissected and processed for RNA-sequencing. As little RNA was obtained from budding cells, a special low-input mRNA library preparation protocol was used. Gene expression profiles of budding as compared with tumour bulk were investigated for established EMT signatures, consensus molecular subtype (CMS), gene set enrichment and pathway analysis. RESULTS: A total of 296 genes were differentially expressed with an FDR <0.05 and a twofold change between tumour bulk and budding regions. Genes that were upregulated in the budding signature were mainly involved in cell migration and survival while downregulated genes were important for cell proliferation. Supervised clustering according to an established EMT gene signature categorised budding regions as EMT-positive, whereas tumour bulk was considered EMT-negative. Furthermore, a shift from CMS2 (epithelial) to CMS4 (mesenchymal) was observed as tumour cells transit from the tumour bulk to the budding regions. CONCLUSIONS: Tumour budding regions are characterised by a phenotype switch compared with the tumour bulk, involving the acquisition of migratory characteristics and a decrease in cell proliferation. In particular, most tumour budding signatures were EMT-positive and switched from an epithelial subtype (CMS2) in the tumour bulk to a mesenchymal subtype (CMS4) in budding cells.
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Divisão Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/genética , Genes de Troca/genética , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células/genética , Neoplasias Colorretais/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Invasividade Neoplásica , Fenótipo , Análise Serial de TecidosAssuntos
Neoplasias Ósseas , Carcinoma Hepatocelular/patologia , Vértebras Cervicais , Hepatite Autoimune/patologia , Neoplasias Hepáticas/patologia , Fígado , Radioterapia/métodos , Biópsia/métodos , Neoplasias Ósseas/patologia , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/patologia , Feminino , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Testes de Função Hepática/métodos , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Remissão Espontânea , Tomografia Computadorizada por Raios X/métodos , Resultado do TratamentoRESUMO
Background and study aim: Typically, pancreatic patient-derived tumor xenografts (PDXs) are established by transplanting large tumor biopsies obtained through invasive surgery approaches into immunocompromised mice. We aimed to develop pancreatic PDXs by transplanting tumor tissue acquired by endoscopic ultrasound (EUS)-guided fine needle biopsies (FNB), assess take rates compared to surgery-derived PDXs, and demonstrate the histological and genetic resemblance to the original tumor. Patients and methods: Biopsies of untreated pancreatic carcinoma were collected at surgery and during EUS and processed to generate PDXs. Results: By centrifugation of FNB-derived tissue prior to engraftment, we achieved an engraftment rate of 60â% (6/10). Despite a decrease in stromal tissue, the general morphology of FNB-derived PDXs was conserved as assessed by histopathology. At the genetic level, somatic mutation and copy number profiles were largely similar to the primary tumor. Conclusion: We show that it is technically feasible to establish pancreatic PDXs using a minimally invasive sampling technique, such as EUS-FNB. Although only a limited amount of tumor tissue was acquired, we obtained results similar to those from surgery-derived PDXs.
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Carcinoma Ductal Pancreático/patologia , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Transplante de Neoplasias/métodos , Transplante de Neoplasias/patologia , Neoplasias Pancreáticas/patologia , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma Ductal Pancreático/genética , Análise Mutacional de DNA , Exoma , Feminino , Dosagem de Genes , Sobrevivência de Enxerto , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Mutação , Neoplasias Pancreáticas/genética , Projetos Piloto , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genéticaAssuntos
Tumores Neuroendócrinos/diagnóstico por imagem , Octreotida/química , Compostos Organometálicos/química , Neoplasias Retais/diagnóstico por imagem , Alumínio/química , Quelantes/química , Compostos Heterocíclicos com 1 Anel/química , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/químicaRESUMO
PURPOSE: To investigate prospectively the safety, tolerability, and efficacy of transarterial chemoembolization using superabsorbent polymer (SAP) microspheres loaded with doxorubicin for the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: During the years 2006-2011, 64 patients underwent 144 transarterial chemoembolization with SAP microspheres procedures. Most of the patients were staged as Barcelona Clinic Liver Cancer class B (65%). The most frequent underlying liver diseases were hepatitis C (35%) and alcoholic liver disease (28%) resulting in Child-Pugh A (73.4%) or Child-Pugh B (17%) liver cirrhosis. Tumor response was assessed using modified Response Evaluation Criteria in Solid Tumors with magnetic resonance (MR) imaging performed 4-6 weeks after each procedure. RESULTS: Serious adverse events (n = 9) were ischemic or infectious in nature. Transarterial chemoembolization with SAP microspheres resulted in objective response rates of 67.5%, 44.5%, and 25% after first, second, and third sessions. There were 16 patients (25%) who underwent orthotopic liver transplantation after transarterial chemoembolization with SAP microspheres, of whom 2 experienced recurrent disease. During a median follow-up time of 14 months (range, 2-55 mo), 26 patients (40.5%) died. Median overall and transplant-free survivals were 20.5 months (95% confidence interval, 13.2-27.7) and 18 months (95% confidence interval, 14.2-21.8), respectively. CONCLUSIONS: Transarterial chemoembolization with SAP microspheres has an excellent safety profile in cirrhotic patients, even in the presence of advanced liver disease (Child-Pugh B) or advanced stages of HCC. This treatment produced meaningful tumor response rates as assessed by MR imaging.
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Antibióticos Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Doxorrubicina/administração & dosagem , Neoplasias Hepáticas/terapia , Polímeros/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/efeitos adversos , Quimioembolização Terapêutica/mortalidade , Intervalo Livre de Doença , Doxorrubicina/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Transplante de Fígado , Imageamento por Ressonância Magnética , Masculino , Microesferas , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polímeros/efeitos adversos , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Carga TumoralRESUMO
We investigated the effect of the Arabidopsis thaliana-derived decapeptide OSIP108 on human cell tolerance to the chemotherapeutic agent cisplatin (Cp), which induces apoptosis and mitochondrial dysfunction. We found that OSIP108 increases the tolerance of HepG2 cells to Cp and prevents Cp-induced changes in basic cellular metabolism. More specifically, we demonstrate that OSIP108 reduces Cp-induced inhibition of respiration, decreases glycolysis and prevents Cp-uptake in HepG2 cells. Apart from its protective action against Cp in human cells, OSIP108 also increases the yeast Saccharomyces cerevisiae tolerance to Cp. A limited yeast-based study of OSIP108 analogs showed that cyclization does not severely affect its activity, which was further confirmed in HepG2 cells. Furthermore, the similarity in the activity of the D-stereoisomer (mirror image) form of OSIP108 with the L-stereoisomer suggests that its mode of action does not involve binding to a stereospecific receptor. In addition, as OSIP108 decreases Cp uptake in HepG2 cells and the anti-Cp activity of OSIP108 analogs without free cysteine is reduced, OSIP108 seems to protect against Cp-induced toxicity only partly via complexation. Taken together, our data indicate that OSIP108 and its cyclic derivatives can protect against Cp-induced toxicity and, thus, show potential as treatment options for mitochondrial dysfunction- and apoptosis-related conditions.
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Antineoplásicos/toxicidade , Proteínas de Arabidopsis/farmacologia , Arabidopsis/fisiologia , Cisplatino/toxicidade , Mitocôndrias/efeitos dos fármacos , Células Hep G2 , Humanos , Mitocôndrias/fisiologiaRESUMO
Primary liver cancer, more specifically hepatocellular carcinoma (HCC), remains a significant global health problem associated with increasing incidence and mortality. Clinical, biological, and molecular heterogeneity are well-known hallmarks of cancer and HCC is considered one of the most heterogeneous tumour types, displaying substantial inter-patient, intertumoural and intratumoural variability. This heterogeneity plays a pivotal role in hepatocarcinogenesis, metastasis, relapse and drug response or resistance. Unimodal single-cell sequencing techniques have already revolutionised our understanding of the different layers of molecular hierarchy in the tumour microenvironment of HCC. By highlighting the cellular heterogeneity and the intricate interactions among cancer, immune and stromal cells before and during treatment, these techniques have contributed to a deeper comprehension of tumour clonality, hematogenous spreading and the mechanisms of action of immune checkpoint inhibitors. However, major questions remain to be elucidated, with the identification of biomarkers predicting response or resistance to immunotherapy-based regimens representing an important unmet clinical need. Although the application of single-cell multi-omics in liver cancer research has been limited thus far, a revolution of individualised care for patients with HCC will only be possible by integrating various unimodal methods into multi-omics methodologies at the single-cell resolution. In this review, we will highlight the different established single-cell sequencing techniques and explore their biological and clinical impact on liver cancer research, while casting a glance at the future role of multi-omics in this dynamic and rapidly evolving field.
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Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are distinct cancer syndromes caused, respectively, by mono- and bi-allelic germline mismatch repair (MMR) variants. LS predisposes to mainly gastrointestinal and genitourinary cancers in adulthood. CMMRD predisposes to brain, haematological, and LS-spectrum cancers from childhood. Two suspected LS patients with first cancer diagnosis aged 27 or 38 years were found to be homozygous for an MMR (likely) pathogenic variant, MSH6 c.3226C>T (p.(Arg1076Cys)), or variant of uncertain significance (VUS), MLH1 c.306G>A (p.(Glu102=)). MLH1 c.306G>A was shown to cause leaky exon 3 skipping. The apparent genotype-phenotype conflict was resolved by detection of constitutional microsatellite instability in both patients, a hallmark feature of CMMRD. A hypomorphic effect of these and other variants found in additional late onset CMMRD cases, identified by literature review, likely explains a LS-like phenotype. CMMRD testing in carriers of compound heterozygous or homozygous MMR VUS may find similar cases and novel hypomorphic variants. Individualised management of mono- and bi-allelic carriers of hypomorphic MMR variants is needed until we better characterise the associated phenotypes.
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[18F]AlF-NOTA-octreotide ([18F]AlF-OC) is a promising alternative for [68Ga]Ga-DOTA-somatostatin analogs (SSAs) in positron emission tomography (PET) imaging of the somatostatin receptor (SSTR). Our aim is to assess changes in TNM staging and differences in patient management between [18F]AlF-OC PET/CT and [68Ga]Ga-DOTA-SSA PET/CT in the work-up of neuroendocrine tumor (NET) patients. Patients who underwent both [18F]AlF-OC and [68Ga]Ga-DOTA-TATE or [68Ga]Ga-DOTA-NOC PET/CT in our multicenter study (Pauwels et al., J Nucl Med.2023;63:632-638) with a NET were included for analysis. TNM staging was determined and compared for both tracers. For each patient, the blinded [68Ga]Ga-DOTA-SSA or [18F]AlF-OC PET/CT images were presented in random order at a multidisciplinary team board. The images were presented together with clinical information and compared with previous SSTR and [18F]FDG PET/CT imaging. After a consensus decision for patient management was recorded, the board was presented with the PET/CT images from the other SSTR tracer and a decision was made for the second tracer. Differences in management were classified as major if it entailed an intermodality change and minor if it led to an intramodality change. Compared with [68Ga]Ga-DOTA-SSA, the use of [18F]AlF-OC led to a change in 16/75 patients: TNM staging changes in 10/75 patients (13.3%; downstaging in 3/10, upstaging in 7/10) and differences in clinical management were seen in 10/75 patients (13.3%), leading to a major difference in 7/10 cases and a minor change in 3/10 cases. All 10 cases with a difference in patient management between both PET tracers were caused by additional lesion detection by [18F]AlF-OC. The use of [18F]AlF-OC did not impact TNM staging or clinical management in the large majority of the patients (86.7%), further validating the potential for routine clinical use of [18F]AlF-OC PET/CT as an alternative for [68Ga]Ga-DOTA-SSA PET/CT. The trial is registered under ClinicalTrials.gov identifier NCT04552847 and EudraCT 2020-000549-15.
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Tumores Neuroendócrinos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Masculino , Pessoa de Meia-Idade , Feminino , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/patologia , Idoso , Estudos Prospectivos , Adulto , Octreotida/análogos & derivados , Compostos Radiofarmacêuticos , Somatostatina/análogos & derivados , Compostos Organometálicos , Radioisótopos de Gálio , Estadiamento de Neoplasias/métodosRESUMO
BACKGROUND: The TOPAZ-1 phase III trial showed a survival benefit with durvalumab plus gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). To understand this combination's real-world efficacy and tolerability, we conducted a global multicenter retrospective analysis of its first-line treatment outcomes. METHODS: We included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab, gemcitabine, and cisplatin at 39 sites in 11 countries (Europe, the United States, and Asia). The primary endpoint was overall survival (OS). RESULTS: 666 patients were enrolled. Median OS was 15.1 months and median PFS was 8.2 months. The investigator-assessed overall response rate was 32.7 %, with stable disease in 45.2 % of patients. High baseline CEA levels, ECOG PS > 0, metastatic disease, and NLR > 3 were associated with poor survival. Any grade adverse events (AEs) occurred in 92.9 % of patients (grade >2: 46.6 %). Immune-related AEs (irAEs) occurred in 20.0 % (grade >2: 2.5 %). Three deaths (0.5 %) were deemed treatment-related, none linked to immunotherapy. Common irAEs were rash (8.2 % all grades; 0.3 % grade >2), itching (10.3 % all grades; 0.2 % grade >2), and hypothyroidism (5.1 % all grades; 0.3 % grade >2). Durvalumab discontinuation rate due to AEs was 1.5 %. ESMO-recommended genes were analyzed and no outcome differences were found. A comparative analysis with a historical cohort of patients treated with chemotherapy alone confirmed the positive survival impact of durvalumab in combination with cisplatin/gemcitabine. CONCLUSION: This first global real-world analysis largely confirmed the TOPAZ-1 findings, supporting gemcitabine, cisplatin, and durvalumab as a first-line standard of care for patients with advanced BTC.
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Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Sistema Biliar , Cisplatino , Desoxicitidina , Gencitabina , Humanos , Masculino , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/patologia , Neoplasias do Sistema Biliar/mortalidade , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Idoso de 80 Anos ou maisRESUMO
PURPOSE OF REVIEW: Hepatocellular carcinoma (HCC) is a prevalent malignancy associated with a guarded prognosis. At present, sorafenib is the only approved systemic therapy for patients with advanced disease. The effect of sorafenib on overall survival is modest and limited in time by the occurrence of drug resistance. RECENT FINDINGS: Together with the increasing knowledge of molecular pathways involved in HCC, targeted molecules have been developed and tested in first and second line following sorafenib. These include antiangiogenic drugs, as well as biologicals inhibiting cell proliferation and survival. Recent phase III trials investigated sunitinib, linifanib, brivanib and erlotinib, but none of them were found superior to sorafenib. New findings in mechanisms of drug resistance create opportunities in the treatment of sorafenib-refractory disease, with cMET inhibition as the most promising approach. This article reviews the pathways involved in HCC and their targets as well as potential strategies for drug development in the future. SUMMARY: Advanced HCC has been the subject of intensive clinical research following the success of sorafenib. Despite many failures, some agents show promising results in phase II trials. Targeting new pathways, using multidrug regimens and tailoring treatment guided by predictive markers should allow new successes.
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Produtos Biológicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/patologia , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Compostos de Fenilureia/uso terapêutico , SorafenibeRESUMO
Primary liver cancer is the third most common cause of cancer-related death worldwide and hepatocellular carcinoma (HCC) accounts for approximately 80%-90% of all primary liver malignancies. Until 2007, there was no effective treatment option available for patients diagnosed with advanced HCC, whereas today, both multireceptor tyrosine kinase inhibitors as well as immunotherapy combinations have entered clinical practice. The choice between the different options is a tailor-made decision to match the efficacy and safety data of the clinical trials with the specific patient and disease profile. This review provides clinical stepstones to make an individualized decision for every patient with its specific tumor and liver characteristics in mind.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Imunoterapia , Resultado do TratamentoRESUMO
Tyrosine kinase inhibitors (TKIs) with antiangiogenic properties, such as sorafenib, have been the standard choice to systemically treat hepatocellular carcinoma for over a decade. More recently, encouraging results were obtained using immune checkpoint inhibitors, although head-to-head comparisons with sorafenib in phase 3 trials could not demonstrate superiority in terms of overall survival. The IMbrave150 was a breakthrough study that resulted in atezolizumab/bevacizumab, a combination of an antiangiogenic and an immune checkpoint inhibitor, as a new standard of care for advanced HCC. This review discusses the mode of action, clinical efficacy, and biomarker research for both drug classes and for the combination therapy. Moreover, the synergy between atezolizumab and bevacizumab is highlighted, unraveling pathophysiological mechanisms underlying an enhanced anticancer immunity by changing the immunosuppressed to a more immunoreactive tumor microenvironment (TME). This is achieved by upregulation of antigen presentation, upregulation of T-cell proliferation, trafficking and infiltration, impairing recruitment, and proliferation of immunosuppressive cells in the TME. However, more insights are needed to identify biomarkers of response that may improve patient selection and outcome.
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Surgery is the primary component of curative treatment for patients with rectal cancer. However, patients with a clinical complete response (cCR) after neo-adjuvant treatment may avoid the morbidity and mortality of radical surgery. An organ-sparing strategy could be an oncological equivalent alternative. Therefore, shared decision making between the patient and the healthcare professional (HCP) should take place. This can be facilitated by a patient decision aid (PtDA). In this study, we developed a PtDA based on a literature review and the key elements of the Ottawa Decision Support Framework. Additionally, a qualitative study was performed to review and evaluate the PtDA by both HCPs and former rectal cancer patients by a Delphi procedure and semi-structured interviews, respectively. A strong consensus was reached after the first round (I-CVI 0.85-1). Eleven patients were interviewed and most of them indicated that using a PtDA in clinical practice would be of added value in the decision making. Patients indicated that their decisional needs are centered on the impact of side effects on their quality of life and the outcome of the different options. The PtDA was modified taking into account the remarks of patients and HCPs and a second Delphi round was held. The second round again showed a strong consensus (I-CVI 0.87-1).
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INTRODUCTION: Current available systemic therapies for advanced cholangiocarcinoma (CCA) are of limited effectiveness and prognosis is poor. Recently, introduction of next-generation sequencing (NGS) technologies led to a better understanding of the genetic pathophysiology and, consequently, identification of molecular alterations for targeted treatment. AIM: To determine the proportion of actionable alterations using extensive molecular profiling in a routine diagnostic setting and to study the effect of targeted treatment on disease control. METHODS: Results of extensive molecular testing by either FoundationOne NGS or an in-house developed 96 cancer gene panel were retrospectively collected from patients with locally advanced or metastatic CCA diagnosed between 01/12/2018 and 01/08/2021 in a single center. Gene variants were classified according to ESCAT and correlated with efficacy endpoints. RESULTS: Of 125 patients included, 65 patients had an intrahepatic CCA (iCCA). FGFR2 fusions and IDH1/BAP1 mutations were more frequent in iCCA, while KRAS and SMAD4 mutations were predominant in extrahepatic CCA (eCCA). Targetable alterations (ESCAT tiers I-IV) were identified in 73,6% of patients. Overall survival was significantly better for higher tiers regardless of treatment. Thirteen patients (10.4%) received targeted treatment based on molecular profiling, with a median progression-free survival (PFS) of 7.3 months. CONCLUSIONS: Extensive molecular characterization led to the identification of targetable and potentially targetable alterations in a significant proportion of patients with locally advanced or metastatic CCA. We confirmed the association between higher ESCAT tier and benefit of a targeted treatment. Molecular analysis should therefore be considered in all patients fit enough for systemic treatment.