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BACKGROUND: Hip fracture patients face a patient safety threat due to medication discrepancies and adverse drug reactions when they have a combination of high age, polypharmacy and several care transitions. Consequently, optimised pharmacotherapy through medication reviews and seamless communication of medication information between care settings is necessary. The primary aim of this study was to investigate the impact on medication management and pharmacotherapy. The secondary aim was to evaluate implementation of the novel Patient Pathway Pharmacist intervention for hip fracture patients. METHODS: Hip fracture patients were included in this nonrandomised controlled trial, comparing a prospective intervention group (n = 58) with pre-intervention controls who received standard care (n = 50). The Patient Pathway Pharmacist intervention consisted of the steps: (A) medication reconciliation at admission to hospital, (B) medication review during hospitalisation, (C) recommendation for the medication information in the hospital discharge summary, (D) medication reconciliation at admission to rehabilitation, and (E) medication reconciliation and (F) review after hospital discharge. The primary outcome measure was quality score of the medication information in the discharge summary (range 0-14). Secondary outcomes were potentially inappropriate medications (PIMs) at discharge, proportion receiving pharmacotherapy according to guidelines (e.g. prophylactic laxatives and osteoporosis pharmacotherapy), and all-cause readmission and mortality. RESULTS: The quality score of the discharge summaries was significantly higher for the intervention patients (12.3 vs. 7.2, p < 0.001). The intervention group had significantly less PIMs at discharge (- 0.44 (95% confidence interval - 0.72, - 0.15), p = 0.003), and a higher proportion received prophylactic laxative (72 vs. 35%, p < 0.001) and osteoporosis pharmacotherapy (96 vs. 16%, p < 0.001). There were no differences in readmission or mortality 30 and 90 days post-discharge. The intervention steps were delivered to all patients (step A, B, E, F = 100% of patients), except step (C) medication information at discharge (86% of patients) and step (D) medication reconciliation at admission to rehabilitation (98% of patients). CONCLUSION: The intervention steps were successfully implemented for hip fracture patients and contributed to patient safety through a higher quality medication information in the discharge summary, fewer PIMs and optimised pharmacotherapy. TRIAL REGISTRATION: NCT03695081.
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Fraturas do Quadril , Osteoporose , Humanos , Farmacêuticos , Assistência ao Convalescente , Estudos Prospectivos , Alta do Paciente , Fraturas do Quadril/tratamento farmacológicoRESUMO
OBJECTIVE: Patients with hip fracture are at high risk of medication errors due to a combination of high age, comorbidities, polypharmacy and several care transitions after fracture. The aim was to study medication management tasks concerning patient safety: medication reconciliation, medication review and communication of key medication information in care transitions. DESIGN: Descriptive study comprising a self-administered clinician survey (MedHipPro-Q) and a retrospective review of hospital medical records of patients with hip fracture. SETTING: Regional hospital and the associated primary care units (South-Eastern Norway). PARTICIPANTS: The survey received responses from 253 clinicians, 61 medical doctors and 192 nurses, involved in the medication management of patients with hip fracture, from acute admittance to the regional hospital, through an in-hospital fast track, primary care rehabilitation and back to permanent residence. Respondents' representativeness was unknown, introducing a risk of selection and non-response bias, and extrapolating findings should be done with caution. The patient records review included a random sample of records of patients with hip fracture (n=50). OUTCOME MEASURES: Medication reconciliation, medication review and communication of medication information from two perspectives: the clinicians' (ie, experiences with medication management) and the practice (ie, documentation of completed medication management). RESULTS: In the survey, most clinicians stated they performed medication reconciliation (79%) and experienced that patients often arrived without a medication list after care transition (37%). Doctors agreed that more patients would benefit from medication reviews (86%). In the hospital patient records, completed medication reconciliation was documented in most patients (76%). Medication review was documented in 2 of 50 patients (4%). Discharge summary guidelines were followed fully for 3 of 50 patients (6%). CONCLUSION: Our study revealed a need for improved medication management for patients with hip fracture. Patients were at risk of medication information not being transferred correctly between care settings, and medication reviews seemed to be underused in clinical practice.
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Reconciliação de Medicamentos , Conduta do Tratamento Medicamentoso , Humanos , Prontuários Médicos , Transferência de Pacientes , Hospitais , Inquéritos e Questionários , Alta do PacienteRESUMO
BACKGROUND: Matching treatment based on tumour molecular characteristics has revolutionized the treatment of some cancers and has given hope to many patients. Although personalized cancer care is an old concept, renewed attention has arisen due to recent advancements in cancer diagnostics including access to high-throughput sequencing of tumour tissue. Targeted therapies interfering with cancer specific pathways have been developed and approved for subgroups of patients. These drugs might just as well be efficient in other diagnostic subgroups, not investigated in pharma-led clinical studies, but their potential use on new indications is never explored due to limited number of patients. METHODS: In this national, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled in multiple parallel cohorts. Each cohort is defined by the patient's tumour type, molecular profile of the tumour, and study drug. Treatment outcome in each cohort is monitored by using a Simon two-stage-like 'admissible' monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Molecular diagnostics are funded by the public health care system. DISCUSSION: Precision oncology means to stratify treatment based on specific patient characteristics and the molecular profile of the tumor. Use of targeted drugs is currently restricted to specific biomarker-defined subgroups of patients according to their market authorization. However, other cancer patients might also benefit of treatment with these drugs if the same biomarker is present. The emerging technologies in molecular diagnostics are now being implemented in Norway and it is publicly reimbursed, thus more cancer patients will have a more comprehensive genomic profiling of their tumour. Patients with actionable genomic alterations in their tumour may have the possibility to try precision cancer drugs through IMPRESS-Norway, if standard treatment is no longer an option, and the drugs are available in the study. This might benefit some patients. In addition, it is a good example of a public-private collaboration to establish a national infrastructure for precision oncology. Trial registrations EudraCT: 2020-004414-35, registered 02/19/2021; ClinicalTrial.gov: NCT04817956, registered 03/26/2021.
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Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Humanos , Oncologia , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisão , Estudos ProspectivosRESUMO
Pseudomyxoma peritonei (PMP) is a rare, slow-growing cancer characterized by progressive accumulation of intraperitoneal mucinous tumor deposits. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) cures approximately 50% of patients, but in unresectable and recurrent cases, treatment options are limited. Anti-angiogenic treatment is being explored as a potential therapeutic option. Using PMP patient samples, microvessel densities (immunostaining for CD31 and CD105) and pro-angiogenic factors were analyzed, and the proliferative response upon incubation with human umbilical cord vascular endothelial cells (HUVEC) was determined. Growth inhibition by anti-angiogenic drugs was analyzed in patient-derived xenograft models of PMP. PMP tumor tissues were found to be highly vascularized and contained key pro-angiogenic factors, in particular related to vascular endothelial growth factor (VEGF) signaling, but interestingly, high levels of fibroblast growth factor 2 were also detected. HUVEC proliferation was stimulated upon incubation with fresh tumor samples and the observed proliferation could be inhibited by VEGF pathway inhibitor bevacizumab. In xenograft models the two VEGF pathway inhibitors, bevacizumab and aflibercept, inhibited tumor growth. This work reemphasizes the importance of angiogenesis as a major driver in PMP and strengthens the preclinical rationale for continued exploration of angiogenesis inhibition in the hope of providing novel treatment to a group of patients that have few other treatment options.
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BACKGROUND: Despite extensive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), most patients with resectable peritoneal metastases from colorectal cancer experience disease relapse. MOC31PE immunotoxin is being explored as a novel treatment option for these patients. MOC31PE targets the cancer-associated epithelial cell adhesion molecule, and kills cancer cells by distinct mechanisms, simultaneously causing immune activation by induction of immunogenic cell death (ICD). METHODS: Systemic and local cytokine responses were analyzed in serum and intraperitoneal fluid samples collected the first three postoperative days from clinically comparable patients undergoing CRS-HIPEC with (n = 12) or without (n = 26) intraperitoneal instillation of MOC31PE. A broad panel of 27 pro- and antiinflammatory interleukins, chemokines, interferons, and growth factors was analyzed using multiplex technology. RESULTS: The time course and magnitude of the systemic and local postoperative cytokine response after CRS-HIPEC were highly compartmentalized, with modest systemic responses contrasting substantial intraperitoneal responses. Administration of MOC31PE resulted in changes that were broader and of higher magnitude compared with CRS-HIPEC alone. Significantly increased levels of innate proinflammatory cytokines, such as interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF) as well as an interesting time response curve for the strong T-cell stimulator interferon (IFN)-γ and its associated chemokine interferon gamma-induced protein/chemokine (C-X-C motif) ligand 10 (IP-10) were detected, all associated with ICD. CONCLUSIONS: Our study revealed a predominately local rather than systemic inflammatory response to CRS-HIPEC, which was strongly enhanced by MOC31PE treatment. The MOC31PE-induced intraperitoneal inflammatory reaction could contribute to improve remnant cancer cell killing, but the mechanisms remain to be elucidated in future studies.
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Neoplasias Colorretais , Hipertermia Induzida , Neoplasias Peritoneais , Neoplasias Colorretais/tratamento farmacológico , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , Humanos , Quimioterapia Intraperitoneal Hipertérmica , Imunoconjugados , Neoplasias Peritoneais/tratamento farmacológicoRESUMO
BACKGROUND: The ImmunoPeCa trial investigated the use of intraperitoneal MOC31PE immunotoxin as a novel therapeutic principle for the treatment of peritoneal metastasis from colorectal cancer (PM-CRC). We here report long-term outcome from the trial. METHODS: This was a dose-finding trial aiming to evaluate safety and toxicity (primary endpoint) upon a single dose of intraperitoneal MOC31PE in patients with PM-CRC undergoing CRS-HIPEC with mitomycin C. Overall survival (OS) and disease-free survival (DFS) were secondary endpoints. Twenty-one patients received the study drug at four dose levels on the first postoperative day, including six patients constituting an expansion cohort. RESULTS: With a 34-month follow-up, the median OS was not reached and the estimated 3-year OS was 78%. Median DFS for all patients was 21 months and the 3-year DFS was 33%, with a median follow-up of 31 months. When excluding patients with potential favorable characteristics from the analysis (nâ¯=â¯4), the median DFS was 13 months and the 3-year OS 72%. CONCLUSIONS: The promising long-term outcome combined with low systemic absorbance, high drug concentration and cytotoxic activity in peritoneal fluid support further investigations of clinical efficacy.
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Neoplasias Colorretais/patologia , Imunoconjugados/uso terapêutico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/secundário , Adulto , Idoso , Antibióticos Antineoplásicos/uso terapêutico , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , Feminino , Humanos , Quimioterapia Intraperitoneal Hipertérmica , Masculino , Pessoa de Meia-Idade , Mitomicina/uso terapêutico , Noruega , Neoplasias Peritoneais/cirurgiaRESUMO
B7-H3 and EpCAM are overexpressed in cancer and play a role in tumorigenesis and metastasis. In this study, the membranous, cytoplasmic and nuclear expression levels of B7-H3 and EpCAM biomarkers were mapped in three major subtypes of renal cell carcinoma (RCC). Expression of B7-H3 and EpCAM were evaluated using immunohistochemistry in RCC samples on tissue microarrays (TMAs), including clear cell RCCs (ccRCCs), type I and II papillary RCCs (pRCCs), and chromophobe RCCs (chRCCs). The association between B7-H3 and EpCAM expression and clinicopathological features as well as survival outcomes was determined. There was a statistically significant difference between B7-H3 and EpCAM expression among the different RCC subtypes. In ccRCC, higher cytoplasmic expression of B7-H3 was significantly associated with increase in nucleolar grade, lymph node invasion (LNI), invasion of the Gerota's fascia, and tumor necrosis, while no association was found with the membranous and nuclear expression. Moreover tumors with cytoplasmic expression of B7-H3 tended to have a worse prognosis for disease-specific survival (DSS) than those with membranous expression. In case of EpCAM, increased membranous expression of EpCAM was associated with nucleolar grade and tumor necrosis in ccRCC. Additionally, membranous EpCAM expression added prognostic value in patients with ccRCC who had high nucleolar grade versus low nucleolar grade. Moreover, membranous EpCAM expression was found to be an independent favorable prognostic marker for progression-free survival (PFS) in ccRCC. Our results demonstrated that higher cytoplasmic B7-H3 and membranous EpCAM expression are clinically significant in ccRCC and are associated with more aggressiveness tumor behavior.
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Antígenos B7/biossíntese , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/patologia , Molécula de Adesão da Célula Epitelial/biossíntese , Neoplasias Renais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/mortalidade , Membrana Celular/metabolismo , Citoplasma/metabolismo , Feminino , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Introduction: In a recent phase I trial in a heterogeneous group of carcinoma patients with advanced disease, we did not observe objective responses by CT at 8 weeks in patients treated with either the anti-EpCAM immunotoxin MOC31PE alone or administered in combination with the immunosuppressor cyclosporin (CsA). We have now assessed overall survival (OS) data for the two groups to reveal potential differences, and to elucidate putative underlying mechanisms.Material and methods: The OS time of MOC31PE monotherapy (34 patients) and MOC31PE in combination with CsA (23 patients), was assessed. Pre- and post-treatment patient sera were analyzed in a multiplex immunoassay, and the immunogenic effects of MOC31PE were studied in vitro and in a dendritic cell maturation assay.Results: When the data were analyzed for all treated patients regardless of cancer type, the MOC31PE alone group had a median OS of 12.7 months (95% CI = 5.6-19.8 months) compared to 6.2 months (95% CI = 5.6-6.8 months) (p=.066) for the patients treated with MOC31PE + CsA group. For the subgroup of patients with colorectal cancer, the median OS survival was 16.3 months (95% CI = 5.6-27.0) for the MOC31PE only cohort (n = 15), compared to 6.0 months (CI = 5.8-6.2) (p < .001) for the combination group. The cytokine profile in patient sera and the in vitro immunological studies indicate that MOC31PE induced an immunogenic response leading to T-cell activation; a response that was suppressed in patients treated with MOC31PE + CsA.Conclusions: The results reveal a promising clinical benefit of anti-EpCAM immunotoxin treatment in patients with advanced disease, an effect apparently explained by a previously unknown immunogenic effect of MOC31PE.
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Neoplasias Colorretais/mortalidade , Ciclosporina/uso terapêutico , Molécula de Adesão da Célula Epitelial/antagonistas & inibidores , Imunoconjugados/uso terapêutico , Imunotoxinas/uso terapêutico , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Molécula de Adesão da Célula Epitelial/imunologia , Molécula de Adesão da Célula Epitelial/metabolismo , Humanos , Imunossupressores/uso terapêutico , Metástase Neoplásica , Prognóstico , Taxa de SobrevidaRESUMO
Intravitreal injections of antibody-based biologics targeting vascular endothelial growth factor (VEGF) are highly effective and have markedly decreased the risk of visual impairment associated with prevalent retinal diseases, such as neovascular age-related macular degeneration and diabetes macular oedema. The diseases are chronic in their nature, and most patients need long-term therapy to suppress disease activity. We previously reported a compounding method for repackaging and storage of aflibercept (Eylea), a commonly used anti-VEGF biologic, in silicone oil-coated plastic syringes without compromising drug stability or activity. In addition to improving safety and time spent per patient, compounding of anti-VEGF biologics enables single-dose vials to be split into multiple syringes, thereby considerably reducing waste and drug expenses. However, symptomatic silicone oil droplets may deposit in the eye's vitreous body after repetitive injections. To fully avoid this complication, we here report on a novel pharmaceutical compounding method using silicone oil-free syringes and a 33 G × 9 mm Low Dead Space Needle hub injection needle. We evaluate the method for three anti-VEGF biologics commonly used in ophthalmology: aflibercept, ranibizumab (Lucentis) and bevacizumab (Avastin). Our results show that compounding and storage for one week does not compromise the functional activity of the biologics and allows for safe and cost-effective compounding of anti-VEGF biologics for intravitreal injections in prefilled silicone oil-free syringes.
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Inibidores da Angiogênese/química , Produtos Biológicos/química , Composição de Medicamentos/métodos , Armazenamento de Medicamentos/métodos , Seringas , Inibidores da Angiogênese/administração & dosagem , Produtos Biológicos/administração & dosagem , Química Farmacêutica , Retinopatia Diabética/tratamento farmacológico , Estabilidade de Medicamentos , Humanos , Injeções Intravítreas , Degeneração Macular/tratamento farmacológico , Edema Macular/tratamento farmacológico , Oxirredução , Plásticos , Óleos de Silicone/química , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
BACKGROUND: Nurses are frequently required to undertake generic substitution of drugs in hospitals. According to the prevailing regulations, nurses may only undertake such substitution based on the Norwegian Medicines Agency's substitution list or the local substitution list in the hospital's quality system. MATERIAL AND METHOD: A total of 600 nurses in 23 surgical and 28 medical wards in three health trusts were invited to participate in an online questionnaire survey on the generic substitution of drugs in hospitals. The study was undertaken to assess how current practice functions with regard to risk factors, documentation and potential improvements. RESULTS: The response rate for the survey was 52 %. A total of 57 % of nurses undertook generic substitution of drugs on a daily basis, while 8 % equally often left the decision to the doctor. In six hypothetical examples of generic substitution, the median number of incorrect responses by the nurses was two; the local substitution list was used as the only source of information in 23 % of cases, and none of the nurses used the Norwegian Medicines Agency's online substitution list. Altogether 37 % responded that generic substitution was recorded in 80 % or more of cases, while 18 % responded that a double-check was performed in 80 % or more of cases. INTERPRETATION: Generic substitution in hospitals entails a significant possibility of errors. Safety and documentation of generic substitution should primarily be taken care of by computerised solutions, with the introduction of an electronic medication chart. Alternatively, the approved substitution list should be the only source used for substitution.
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Substituição de Medicamentos/normas , Enfermeiras e Enfermeiros/normas , Documentação/normas , Hospitais , Humanos , Erros Médicos , Noruega , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
In recent years, the common and mundane dying has begun to take place in the public space of the Internet. Among the blogs about food, fashion, travel, and other joyful aspects of life, blogs about severe disease and dying have appeared. The aim of this article is to describe some characteristic features of a sample of cancer blogs and to discuss them in the light of Zygmunt Bauman's theory of the rationalization of death in modernity and theories about networked media, especially the theories about "affective labor" and "ambient intimacy" by McCosker, Darcy, and Pfister. It will then be argued that an affective communication is performed in and through these cancer blogs, where not only language but also the deficiencies of language-and what is called shared ineffability-might be valuable and meaningful (although not unproblematic) as part of a late modern approach to death, and in the practicing of the art of dying.
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Atitude Frente a Morte , Blogging , Neoplasias/psicologia , Humanos , SuéciaRESUMO
Cancer stem cells (CSCs) are a theorized small subpopulation of cells within tumors thought to be responsible for metastasis, tumor development, disease progression, treatment-resistance, and recurrence. The identification, isolation, and biological characterization of CSCs may therefore facilitate the development of efficient therapeutic strategies targeting CSCs. This study aims to compare the biology and telomerase activity of CSCs to parental cells (PCs) in renal cancer. Renal CSCs were enriched from the ACHN cell line using a sphere culture system. Spheroid-derived cells (SDCs) and their adherent counterparts were compared with respect to their colony and sphere formation, expression of putative CSC markers, tumorigenicity in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, and invasiveness. The expression of genes associated with CSCs, stemness, EMT, apoptosis, and ABC transporters was also compared between the two populations using quantitative real-time PCR (qRT-PCR). Finally, telomerase activity, hTERT expression, and sensitivity to MST-312, a telomerase inhibitor, was investigated between the two populations. We demonstrated that a subpopulation of ACHN cells was capable of growing as spheroids with many properties similar to CSCs, including higher clonogenicity, superior colony- and sphere-forming ability, and stronger tumorigenicity and invasiveness. In addition, SDCs demonstrated a higher expression of markers for CSCs, stemness, EMT, apoptosis, and ABC transporter genes compared to PCs. The expression of hTERT and telomerase activity in SDCs was significantly lower than PCs; however, the SDC population was more sensitive to MST-312 compared to PCs. These findings indicate that the SDC population exhibits stem-like potential and invasive characteristics. Moreover, the reduced expression of hTERT and telomerase activity in SDCs demonstrated that the expressions of hTERT and telomerase activity are not always higher in CSCs. Our results also showed that MST-312 treatment inhibited SDCs more strongly than PCs and may therefore be useful as a complementary targeted therapy against renal CSCs in the future.
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AIM: Although CD44 has been suggested as a prognostic marker in renal cell carcinoma (RCC), the prognostic significance of this marker in three main subtypes of RCC is still unclear. Thus, the present study was conducted to evaluate the expression and prognostic significance of CD44 as a cancer stem cell marker in different histological subtypes of RCC. Methodology & results: CD44 expression was evaluated in 206 well-defined renal tumor samples using immunohistochemistry on tissue microarrays. Higher CD44 expression was associated with more aggressive behavior, tumor progression and worse prognosis in clear cell RCC (ccRCC) but not in papillary and chromophobe RCC subtypes. DISCUSSION & CONCLUSION: Cancer stem cell marker CD44 may be a promising target for cancer treatment only in ccRCC.
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Carcinoma de Células Renais/metabolismo , Receptores de Hialuronatos/metabolismo , Neoplasias Renais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/patologia , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Peritoneal metastasis (PM) is an important feature of epithelial ovarian cancer (EOC) and is a frequent site of drug resistant disease recurrence, identifying PM-EOC an important clinical challenge. The MOC31PE immunotoxin targets and kills tumor cells expressing the epithelial cell adhesion molecule (EpCAM), which is highly expressed in EOC, and MOC31PE is being investigated for use in treatment of PM-EOC. The efficacy of MOC31PE treatment alone and in combination with cytotoxic drugs was investigated in two human EpCAM expressing EOC cell lines, B76 and MDHA-2774, in vitro and in corresponding mouse models mimicking PM-EOC. MOC31PE efficaciously killed tumor cells alone and showed equal or superior activity in vitro (paclitaxel, cisplatin, carboplatin) and in vivo (paclitaxel, mitomycin C) compared to the investigated cytotoxic drugs. Additive, or importantly, no antagonistic effects were observed in combination experiments. In ex vivo cell culture, the cytotoxic effect of MOC31PE was studied on freshly isolated surgical EOC samples. All investigated fresh EOC samples expressed EpCAM and MOC31PE effectively reduced cell viability in ex vivo cultures. In conclusion, these results, together with our previous preclinical and clinical experience, support development of MOC31PE for treatment of PM-EOC in combination with currently used cytotoxic drugs.
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Prominin-1 (CD133) is one of the most commonly used markers for cancer stem cells (CSCs), which are characterized by their ability for self-renewal and tumorigenicity. However, the clinical and prognostic significance of CSCs in renal cell carcinoma (RCC) remains unclear. The aim of this study was to investigate the expression patterns and prognostic significance of the cancer stem cell marker CD133 in different histological subtypes of RCC. CD133 expression was evaluated using immunohistochemistry in 193 well-defined renal tumor samples on tissue microarrays, including 136 (70.5%) clear cell renal cell carcinomas (CCRCCs), 26 (13.5%) papillary RCCs, and 31 (16.1%) chromophobe RCCs. The association between CD133 expression and clinicopathological features as well as the survival outcomes was determined. There was a statistically significant difference between CD133 expression among the different RCC subtypes. In CCRCC, higher cytoplasmic expression of CD133 was significantly associated with increase in grade, stage, microvascular invasion (MVI) and lymph node invasion (LNI), while no association was found with the membranous expression. Moreover, on multivariate analysis, TNM stage and nuclear grade were independent prognostic factors for overall survival (OS) in cytoplasmic expression. We showed that higher cytoplasmic CD133 expression was associated with more aggressive tumor behavior and more advanced disease in CCRCC but not in the other examined subtypes. Our results demonstrated that higher cytoplasmic CD133 expression is clinically significant in CCRCC and is associated with increased tumor aggressiveness and is useful for predicting cancer progression.
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Antígeno AC133/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/secundário , Citoplasma/metabolismo , Neoplasias Renais/patologia , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/metabolismo , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Neoplasias Renais/metabolismo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia/metabolismo , Estadiamento de Neoplasias , Prognóstico , Taxa de SobrevidaRESUMO
B7-H3 (CD276) belongs to the B7 family of immunoregulatory proteins and has been implicated in cancer progression and metastasis. In this study, we found that metastatic melanoma cells with knockdown expression of B7-H3 showed modest decrease in proliferation and glycolytic capacity and were more sensitive to dacarbazine (DTIC) chemotherapy and small-molecule inhibitors targeting MAP kinase (MAPK) and AKT/mTOR pathways: vemurafenib (PLX4032; BRAF inhibitor), binimetinib (MEK-162; MEK inhibitor), everolimus (RAD001; mTOR inhibitor), and triciribidine (API-2; AKT inhibitor). Similar effects were observed in melanoma cells in the presence of an inhibitory B7-H3 monoclonal antibody, while the opposite was seen in B7-H3-overexpressing cells. Further, combining B7-H3 inhibition with small-molecule inhibitors resulted in significantly increased antiproliferative effect in melanoma cells, as well as in BRAFV600E mutated cell lines derived from patient biopsies. Our findings indicate that targeting B7-H3 may be a novel alternative to improve current therapy of metastatic melanoma.
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Antígenos B7/metabolismo , Melanoma/tratamento farmacológico , Melanoma/patologia , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Everolimo/farmacologia , Everolimo/uso terapêutico , Técnicas de Silenciamento de Genes , Glicólise , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Melanoma/genética , Terapia de Alvo Molecular , Mutação/genética , Metástase Neoplásica , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , VemurafenibRESUMO
BACKGROUND: MOC31PE immunotoxin was developed to rapidly kill cells expressing the tumor-associated epithelial cell adhesion molecule, which is highly expressed in colorectal cancer. Although cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may offer long-term survival to patients with peritoneal metastasis from colorectal cancer (PM-CRC), most patients experience disease relapse and novel therapeutic options are needed. On this basis, MOC31PE is being developed as a novel therapeutic principle to target PM-CRC. METHODS: This was a dose-escalating phase I trial to evaluate the safety and toxicity (primary endpoint), pharmacokinetic profile, and neutralizing antibody response (secondary endpoints) upon intraperitoneal administration of MOC31PE in patients with PM-CRC undergoing CRS-HIPEC with Mitomycin C. Fifteen patients received the study drug at four dose levels (3+3+3+6), administered intraperitoneally as a single dose the day after CRS-HIPEC. RESULTS: No dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. There was negligible systemic absorption of the study drug. Drug concentrations in peritoneal fluid samples were in the cytotoxic range and increased in a dose-dependent manner. MOC31PE recovered from peritoneal cavity retained its cytotoxic activity in cell-based assays. All patients developed neutralizing antibodies. CONCLUSIONS: Intraperitoneal administration of MOC31PE was safe and well tolerated, and combined with low systemic uptake, MOC31PE seems ideal for local intraperitoneal treatment. The drug will be further evaluated in an ongoing phase II expansion cohort.
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Carcinoma de Células em Anel de Sinete/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Imunoconjugados/uso terapêutico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Carcinoma de Células em Anel de Sinete/imunologia , Carcinoma de Células em Anel de Sinete/patologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Humanos , Imunoconjugados/farmacocinética , Injeções Intraperitoneais , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias Peritoneais/imunologia , Neoplasias Peritoneais/patologia , Prognóstico , Taxa de Sobrevida , Distribuição TecidualRESUMO
BACKGROUND: Locally advanced rectal cancer (LARC) comprises heterogeneous tumours with predominant hypoxic components. The hypoxia-inducible metabolic shift causes microenvironmental acidification generated by carbonic anhydrase IX (CAIX) and facilitates metastatic progression, the dominant cause of failure in LARC. METHODS: Using a commercially available immunoassay, circulating CAIX was assessed in prospectively archived serial serum samples collected during combined-modality neoadjuvant treatment of LARC patients and correlated to histologic tumour response and progression-free survival (PFS). RESULTS: Patients who from their individual baseline level displayed serum CAIX increase above a threshold of 224 pg/ml (with 96 % specificity and 39 % sensitivity) after completion of short-course neoadjuvant chemotherapy (NACT) prior to long-course chemoradiotherapy and definitive surgery had significantly better 5-year PFS (94 %) than patients with below-threshold post-NACT versus baseline alteration (PFS rate of 56 %; p < 0.01). This particular CAIX parameter, ΔNACT, was significantly correlated with histologic ypT0-2 and ypN0 outcome (p < 0.01) and remained an independent PFS predictor in multivariate analysis wherein it was entered as continuous variable (p = 0.04). CONCLUSIONS: Our results indicate that low ΔNACT, i.e., a weak increase in serum CAIX level following initial neoadjuvant treatment (in this case two cycles of the Nordic FLOX regimen), might be used as risk-adapted stratification to postoperative therapy or other modes of intensification of the combined-modality protocol in LARC. TRIAL REGISTRATION: ClinicalTrials.gov NCT00278694.
Assuntos
Antígenos de Neoplasias/sangue , Anidrases Carbônicas/sangue , Terapia Neoadjuvante/métodos , Neoplasias Retais/enzimologia , Neoplasias Retais/terapia , Adulto , Idoso , Anidrase Carbônica IX , Quimiorradioterapia Adjuvante/métodos , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias Retais/sangue , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: The aim of this study was to investigate if specific clinical and histological findings can be related to biopsy complications to enable more closely monitoring patients at high risk. METHODS: Results from 1081 biopsies (994 patients, median age 54.5 years; 896 native and 185 transplant kidney biopsies) were included. Diagnostic quality, morphology, clinical data and complications were prospectively registered. RESULTS: In native kidney biopsies, the most common diagnosis was IgA-nephritis, while in transplant kidney biopsies it was rejection. Patients with IgA-nephritis had a higher risk of major complications (11.7 versus 6.4 %, Odds Ratio (OR) 1.8, Confidence Interval (CI) 1.1-3.2) when compared to patients with other diseases. In native kidney biopsies, patients who experienced major complications had higher degrees of glomerulosclerosis (31 versus 20 %, p = 0.008), whereas in transplant kidney biopsies, patients had higher degrees of interstitial fibrosis (82 versus 33 %, p < 0.001) when compared to patients without major complications. IgA-nephritis-patients had a higher risk of re-biopsies (4.7 versus 1.3 %, OR 4, CI 1.5-11) than patients with other diseases. Patients with native kidneys who needed re-biopsies were younger (42.6 versus 52.3 years, p = 0.031) and had a higher degree of interstitial fibrosis (63 versus 34 %, p = 0.046). CONCLUSIONS: Patients with IgA-nephritis have an increased risk of major biopsy complications. The risk of re-biopsies was higher in younger individuals and in patients with IgA-nephritis.