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BACKGROUND: This trial investigated the hypothesis that the treatment with trabectedin/PLD (TP) to extend the platinum-free interval (TFIp) can improve overall survival (OS) in patients with recurrent ovarian cancer (OC). METHODS: Patients with OC (up to two previous platinum-based lines), with a TFIp of 6-12 months, were randomised to receive carboplatin/PLD (CP) or TP followed by platinum therapy at relapse. The primary endpoint was OS (HR: 0.75). RESULTS: The study enrolled 617 patients. The median TFIp was 8.3 months and 30.3% of patients had received two previous platinum lines. 74% and 73.9% of patients, respectively, received a subsequent therapy (ST) in the CP and TP arm; in the latter TP arm 87.2% of ST was platinum-based, as per protocol. The median OS was 21.4 for CP and 21.9 months for TP (HR 1.13; 95% CI: 0.94-1.35; p = 0.197). Grade 3-5 adverse reactions occurred in 37.1% of patients in the CP arm and 69.7% of patients in the TP arm, and the most frequent were neutropenia (22.8% CP, 39.5% TP), gastrointestinal (7.1% CP, 17.4% TP), hepatic (0.7% CP, 19.1% TP). CONCLUSIONS: This study did not meet the primary endpoint. CP combination remains the standard for patients with recurrent OC and a 6-12 months TFIp; TP is an effective treatment in patients suffering from persistent platinum toxicities. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT01379989.
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Neoplasias Ováricas , Humanos , Femenino , Carboplatino , Trabectedina , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/etiología , Platino (Metal)/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/etiología , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Doxorrubicina , Polietilenglicoles , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Patients with advanced endometrial cancer have a poor prognosis, and treatment options are limited. The investigator-initiated, multicenter, phase II DOMEC trial (NCT03951415) is the first trial to report data on efficacy and safety of combined treatment with PD-L1 and PARP inhibition for advanced endometrial cancer. PATIENTS AND METHODS: Patients with metastatic or recurrent endometrial cancer were enrolled. Patients received durvalumab 1500 mg intravenously q4w and olaparib 300 mg 2dd until disease progression, unacceptable toxicity, or patient withdrawal. Patients with at least 4 weeks of treatment were evaluable for analysis. The primary endpoint was progression-free survival at 6 months. Evidence for efficacy was defined as progression-free survival at 6 months in ≥50% of patients. Secondary endpoints included safety, objective response and overall survival. RESULTS: From July 2019, through November 2020, 55 patients were enrolled. At data cut-off (September 2021), 4 of the 50 evaluable patients were still on treatment. Seventeen patients (34%) were progression-free at 6 months. Objective response rate was 16% (95% CI, 8.3 to 28.5) with 1 complete and 7 partial responses. With a median follow-up of 17.6 months, median progression-free survival was 3.4 months (95% CI, 2.8 to 6.2) and median overall survival was 8.0 months (95% CI, 7.5 to 14.3). Grade 3 treatment-related adverse events occurred in 8 patients (16%), predominantly anemia. There were no grade 4 or 5 treatment-related adverse events. CONCLUSION: The combination of durvalumab and olaparib was well tolerated, but did not meet the prespecified 50% 6-month progression-free survival in this heterogeneous patient population with advanced endometrial cancer.
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Neoplasias Endometriales , Recurrencia Local de Neoplasia , Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/etiología , Femenino , Humanos , Recurrencia Local de Neoplasia/patología , Ftalazinas , PiperazinasRESUMEN
This manuscript reports the consensus statements on designing clinical trials in rare ovarian tumours reached at the fifth Ovarian Cancer Consensus Conference (OCCC) held in Tokyo, November 2015. Three important questions were identified concerning rare ovarian tumours (rare epithelial ovarian cancers (eOC), sex-cord stromal tumours (SCST) and germ cell tumours (GCT)): (i) What are the research and trial issues that are unique to rare ovarian tumours? There is a lack of randomised phase III data defining standards of care which makes it difficult to define control arms, but identifies unmet needs that merit investigation. Internationally agreed upon diagnostic criteria, expert pathological review and translational research are crucial. (ii) What should be investigated in rare eOC, GCT and SCST? Trials dedicated to each rare ovarian tumour should be encouraged. Nonetheless, where the question is relevant, rare eOC can be included in eOC trials but with rigorous stratification. Although there is emerging evidence suggesting that rare eOC have different molecular profiles, trials are needed to define new type-specific standards for each rare eOC (clear cell, low grade serous and mucinous). For GCTs, a priority is reducing toxicities from treatment while maintaining cure rates. Both a robust prognostic scoring system and more effective treatments for de novo poor prognosis and relapsed GCTs are needed. For SCSTs, validated prognostic markers as well as alternatives to the current standard of bleomycin/etoposide/cisplatin (BEP) should be identified. (iii) Are randomised trials feasible? Randomised controlled trials (RCT) should be feasible in any of the rare tumours through international collaboration. Ongoing trials have already demonstrated the feasibility of RCT in rare eOC and SCST. Mucinous OC may be considered for inclusion, stratified, into RCTs of non-gynaecological mucinous tumours, while RCTs in high risk or relapsed GCT may be carried out as a subset of male and/or paediatric germ cell studies.
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Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Proyectos de Investigación , Femenino , HumanosRESUMEN
Westermann and Buchholz [(2015). J. Acoust. Soc. Am. 137(2), 757-767] found substantial improvements in speech reception thresholds (SRTs) for normal hearing listeners in a reverberant auditorium when the target talker was separated in distance from a two-talker masker. This study applied similar methodology, but tested listeners with a hearing impairment. On average, the participants received a 7 dB benefit in SRTs when the target was fixed at 0.5 m and the masker was moved from 0.5 to 10 m. But when the target was moved away, the SRTs increased by 5 dB. This indicates that hearing impaired listeners have difficulties suppressing nearby maskers while focusing attention on a far target.
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Dermatomycoses due to pets and farm animals are often a clinical and diagnostic challenge for dermatologists. A 24-year-old man presented with inflammatory skin changes on his cheeks and chin. Because of negative fungal culture and the clinical appearance of a highly inflammatory process, our first diagnosis was a bacterial pyoderma. Polymerase chain reaction (PCR) identified Arthroderma benhamiae in both the patient and his guinea pig. A. benhamiae is a zoophilic dermatophyte which belongs to the Trichophyton mentagrophytes-complex. The fungus is acquired from guinea pigs and causes highly inflammatory forms of tinea. PCR-based diagnostics are quick and simple tools to identify this pathogen, so that suitable antimycotic therapy can be initiated quickly.
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Arthrodermataceae/aislamiento & purificación , Dermatomicosis/diagnóstico , Dermatomicosis/veterinaria , Dermatosis Facial/diagnóstico , Cobayas/microbiología , Animales , Dermatomicosis/microbiología , Diagnóstico Diferencial , Dermatosis Facial/microbiología , Dermatosis Facial/veterinaria , Humanos , Masculino , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: On the basis of promising results that were reported in several phase 2 trials, we investigated whether the addition of the monoclonal antibody rituximab to first-line chemotherapy with fludarabine and cyclophosphamide would improve the outcome of patients with chronic lymphocytic leukaemia. METHODS: Treatment-naive, physically fit patients (aged 30-81 years) with CD20-positive chronic lymphocytic leukaemia were randomly assigned in a one-to-one ratio to receive six courses of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days of each 28-day treatment course with or without rituximab (375 mg/m(2) on day 0 of first course, and 500 mg/m(2) on day 1 of second to sixth courses) in 190 centres in 11 countries. Investigators and patients were not masked to the computer-generated treatment assignment. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00281918. FINDINGS: 408 patients were assigned to fludarabine, cyclophosphamide, and rituximab (chemoimmunotherapy group) and 409 to fludarabine and cyclophosphamide (chemotherapy group); all patients were analysed. At 3 years after randomisation, 65% of patients in the chemoimmunotherapy group were free of progression compared with 45% in the chemotherapy group (hazard ratio 0·56 [95% CI 0·46-0·69], p<0·0001); 87% were alive versus 83%, respectively (0·67 [0·48-0·92]; p=0·01). Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (136 [34%] of 404 vs 83 [21%] of 396; p<0·0001) and leucocytopenia (97 [24%] vs 48 [12%]; p<0·0001). Other side-effects, including severe infections, were not increased. There were eight (2%) treatment-related deaths in the chemoimmunotherapy group compared with ten (3%) in the chemotherapy group. INTERPRETATION: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab improves progression-free survival and overall survival in patients with chronic lymphocytic leukaemia. Moreover, the results suggest that the choice of a specific first-line treatment changes the natural course of chronic lymphocytic leukaemia. FUNDING: F Hoffmann-La Roche.
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Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales de Origen Murino , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Factores Inmunológicos/administración & dosificación , Incidencia , Estimación de Kaplan-Meier , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Rituximab , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/análogos & derivadosRESUMEN
BACKGROUND: Combined administration of intravenous (iv) and intraperitoneal (ip) (iv/ip) chemotherapy is an effective adjuvant treatment option after primary debulking surgery (PDS) for advanced ovarian cancer (OC). Increased toxicityand patient burden limit its use in daily practice. OBJECTIVE: To assess toxicity and survival outcomes of iv/ip chemotherapy in daily practice in the Netherlands. METHODS: This retrospective cohort study included 81 women who underwent at least an optimal PDS for FIGO stage III OC followed by iv/ip chemotherapy according to the Armstrong regimen, in four hospitals in the Netherlands between January 2007 and May 2016. We collected information on surgical procedure, abdominal port implantation, toxicity, and recurrence-free and overall survival. RESULTS: All participants underwent PDS, of whom 60 (74%) had their ip catheter implanted during PDS. Most frequently reported all grade toxicity was haematological n = 44 (54%). Forty-four patients (54%) completed all six cycles of iv/ip chemotherapy. The most frequent causes of discontinuation of iv/ip administration were renal dysfunction (12/37 = 32%) and catheter problems (7/37 = 19%). Median recurrence-free survival and overall survival were 24 months (range 0 - 108) and 80 months (range 4-115), respectively. Surgical outcome, completion of more than three courses of treatment and intra-abdominal localisation of recurrent disease were associated with better survival outcomes. CONCLUSION: In daily practice, 54% of patients with advanced OC could complete all scheduled cycles of iv/ ip chemotherapy with acceptable morbidity and toxicity, leading to outcomes comparable with the results of published trials on iv/ip chemotherapy.
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Neoplasias Ováricas , Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Femenino , Humanos , Infusiones Parenterales , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Estudios RetrospectivosRESUMEN
BACKGROUND: This randomized, open-label, phase II clinical trial evaluated the optimal regimen of trabectedin administered every 3 weeks in patients with platinum-sensitive, relapsed, advanced ovarian cancer (AOC). PATIENTS AND METHODS: Patients previously treated with less than two or two previous chemotherapy lines were randomized to receive trabectedin 1.5 mg/m(2) 24 h (arm A, n = 54) or 1.3 mg/m(2) 3 h (arm B, n = 53). Objective response rate (ORR) per RECIST was the primary efficacy end point. Toxic effects were graded according to the National Cancer Institute-Common Toxicity Criteria v. 2.0. RESULTS: ORR was 38.9% [95% confidence interval (CI) 25.9% to 53.1%; arm A] and 35.8% (95% CI 23.1% to 50.2%; arm B) (intention-to-treat primary analysis). Median time to progression was 6.2 months (95% CI 5.3-8.6 months; arm A) and 6.8 months (95% CI 4.6-7.4 months; arm B). Frequent severe adverse events were nausea/vomiting (24%, arm A; 15%, arm B) and fatigue (15%, arm A; 10%, arm B). Common severe laboratory abnormalities were transient, noncumulative neutropenia (55%, arm A; 37%, arm B) and transaminase increases (alanine aminotransferase, 55%, arm A; 59%, arm B). CONCLUSIONS: Both every-3-weeks trabectedin regimes, 1.5 mg/m(2) 24 h and 1.3 mg/m(2) 3 h, were active and reasonably well tolerated in AOC platinum-sensitive patients. Trabectedin every-3-weeks has promising activity and deserves to be further evaluated in relapsed AOC.
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Antineoplásicos Alquilantes/administración & dosificación , Dioxoles/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Tetrahidroisoquinolinas/administración & dosificación , Adulto , Anciano , Antineoplásicos Alquilantes/efectos adversos , Dioxoles/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Compuestos de Platino/uso terapéutico , Tetrahidroisoquinolinas/efectos adversos , TrabectedinaRESUMEN
Background: With the advent of the age of big data in bioinformatics, large volumes of data and high-performance computing power enable researchers to perform re-analyses of publicly available datasets at an unprecedented scale. Ever more studies imply the microbiome in both normal human physiology and a wide range of diseases. RNA sequencing technology (RNA-seq) is commonly used to infer global eukaryotic gene expression patterns under defined conditions, including human disease-related contexts; however, its generic nature also enables the detection of microbial and viral transcripts. Findings: We developed a bioinformatic pipeline to screen existing human RNA-seq datasets for the presence of microbial and viral reads by re-inspecting the non-human-mapping read fraction. We validated this approach by recapitulating outcomes from six independent, controlled infection experiments of cell line models and compared them with an alternative metatranscriptomic mapping strategy. We then applied the pipeline to close to 150 terabytes of publicly available raw RNA-seq data from more than 17,000 samples from more than 400 studies relevant to human disease using state-of-the-art high-performance computing systems. The resulting data from this large-scale re-analysis are made available in the presented MetaMap resource. Conclusions: Our results demonstrate that common human RNA-seq data, including those archived in public repositories, might contain valuable information to correlate microbial and viral detection patterns with diverse diseases. The presented MetaMap database thus provides a rich resource for hypothesis generation toward the role of the microbiome in human disease. Additionally, codes to process new datasets and perform statistical analyses are made available.
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Enfermedad/genética , Metagenómica , Análisis de Secuencia de ARN , Programas Informáticos , Transcriptoma/genética , Humanos , Linfocitos/metabolismoRESUMEN
Eight university medical centres in the Netherlands have established clinical genetic services. Patients receive intensive, and therefore costly, genetic counselling before genetic testing takes place. In recent years the number of patients referred to clinical genetic services has risen dramatically, creating waiting-list backlogs. Knowing your carrier status in hereditary cancers, for instance for a BRCA1/2 mutation, can have consequences for surveillance, treatment, and prevention; however, 90% of patients with breast cancer do not have a mutation. We, therefore, argue that the pathway to genetic testing should be reconstructed in order to safeguard timely and adequate genetic testing for an increasing number of patients. The treating physician should be able to request a DNA test in carefully-selected patient-populations, and only refer patients for genetic counselling after a positive finding. Prerequisites for this 'mainstream pathway' are adequate training for medical specialists, good communication with genetics' departments, and guaranteed referral in uncertain or complex cases.
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Neoplasias de la Mama/genética , Asesoramiento Genético , Pruebas Genéticas , ADN , Humanos , Países BajosRESUMEN
The incidence of endometrial carcinoma is rising and the patients with distant metastases have a poor prognosis, especially when progression of disease occurs after systemic treatment with hormonal therapy or chemotherapy. Pazopanib, a multi-targeted inhibitor of several oncogenic receptor tyrosine kinases, has been investigated in patients with chemotherapy-resistant endometrial carcinoma or patients for whom chemotherapy is contraindicated. In this report we will describe a spectacular response to pazopanib in a patient with recurrent metastatic endometrial carcinoma.
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Pared Abdominal , Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma Endometrioide/tratamiento farmacológico , Neoplasias Endometriales/tratamiento farmacológico , Pirimidinas/uso terapéutico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Carcinoma Endometrioide/secundario , Quimioradioterapia Adyuvante , Neoplasias Endometriales/patología , Femenino , Humanos , Histerectomía , Indazoles , Fístula Intestinal , Persona de Mediana Edad , Metástasis de la Neoplasia , Ovariectomía , Inducción de Remisión , Salpingectomía , Neoplasias de los Tejidos Blandos/secundarioRESUMEN
PURPOSE: To determine the feasibility and safety of multiple, closely timed courses of high-dose cyclophosphamide, thiotepa, and carboplatin (CTC) with peripheral-blood progenitor-cell transplantation (PBPCT). PATIENTS AND METHODS: Forty-eight patients with advanced cancer were scheduled to undergo either two or three courses of CTC with PBPCT. All PBPCs were harvested before high-dose therapy began. Full-dose CTC courses incorporated cyclophosphamide (6,000 mg/m2), thiotepa (480 mg/m2), and carboplatin (1,600 mg/m2) divided over days -6, -5, -4, and -3. Tiny CTC courses (tCTC) contained 67% of the doses of each of these agents. Second or third courses of CTC or tCTC began on day 28. RESULTS: A sufficient number of PBPC could be harvested from all but two patients. Thirty-five first full-dose courses of CTC were given, 28 second courses, and 10 third courses. Second courses could be given on time and at full dose in 80% of the patients, but there was one toxic death from venoocclusive disease (VOD). Only four of 12 patients scheduled to receive three courses of full-dose CTC could be treated at the time and dose planned. There were three toxic deaths: one of VOD, one of sepsis, and one of hemolytic uremic syndrome (HUS). Eight patients were scheduled to receive three courses of tCTC. Eight first, seven second, and six third courses were given. One of the third courses had to be delayed and one had to be reduced in dose. CONCLUSION: A sufficient number of PBPCs for two or three transplantations can be harvested from most patients without much difficulty before high-dose therapy. Two full-dose CTC courses or three tCTC courses can be given safely and with acceptable toxicity at 5-week intervals. Organ toxicity rather than bone marrow toxicity has become dose-limiting for alkylating agents.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Médula Ósea/efectos de los fármacos , Neoplasias de la Mama/terapia , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Estudios de Factibilidad , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Neoplasias de Células Germinales y Embrionarias/terapia , Tiotepa/administración & dosificación , Tiotepa/efectos adversosRESUMEN
BACKGROUND: Studies have shown changes in the technical and physical demands in modern handball. The game has increased considerably in speed, power and dynamics. Jump training has, therefore, become ever more important in the training of the athletes. These developments contribute to the fact that handball is now one of the most injury-prone types of sport, with the lower extremities being most frequently affected. Reactive jump training is not only used in training by now, but also increasingly in injury prevention. The aim of this study was to investigate the effectiveness of reactive jump training with handball players. MATERIAL AND METHODS: 21 regional league handball players were randomly divided into an intervention group (nâ=â12) and a control group (nâ=â9). The intervention group completed a six-week reactive jump training programme while the control group went through a non-specific training programme. Jump height (squat and counter movement jump), isokinetic and isometric maximum power as well as muscle activity served as measuring parameters. RESULTS: A comparison of the intervention and control groups revealed that the reactive jump training led to significant improvements in jump height. The isometric and isokinetic maximum power measurements and the electromyographic activities of the triceps surae muscle demonstrated an improvement in the values within the intervention group. However, this improvement was not significant compared with the control group. Likewise both jumps correlated with the muscle activity of the soleus muscle as shown by electromyography. A moderate correlation was noticed between the isokinetic maximum power measurement and the electromyographic activity of the soleus and gastrocnemius medialis muscles. Furthermore, the correlations of the isometric and isokinetic maximum power meas-urements resulted in a strong correlation coefficient. CONCLUSION: This study revealed a significant increase in jump height after reactive jump training. There was no significant difference in power development between the two groups. However, we were able to demonstrate correlations which would make it seem reasonable and interesting to investigate the question more closely. An interesting field of research could be the question of the effectiveness of reactive jump training in the areas of rehabilitation and injury prevention.
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Rendimiento Atlético/fisiología , Fuerza Muscular/fisiología , Músculo Esquelético/fisiología , Acondicionamiento Físico Humano/métodos , Deportes/fisiología , Adulto , Humanos , Masculino , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Resultado del Tratamiento , Adulto JovenRESUMEN
The role of CpG methylation in the regulation of tissue-specific gene expression is highly controversial. Cyclin A1 is a tissue-specifically expressed gene that is strongly methylated in non-expressing tumor cell lines. We have established a novel real-time PCR method to quantitate genomic CpG methylation of the cyclin A1 promoter. Genomic DNA samples from different human organs were treated with bisulfite and amplified with methylation-specific primers and with primers amplifying methylated as well as non-methylated DNA. PCR product quantitation was obtained by using a fluorogenic probe labeled with FAM and TAMRA. These analyses demonstrated that the human cyclin A1 promoter was methylated in kidney, colon, spleen, testis, and small intestine, but not in brain, liver, pancreas, or heart. Expression of cyclin A1 was predominantly found in testis. Low level expression of cyclin A1 was present in spleen, prostate, leukocytes, colon, and thymus. Taken together, our data provide evidence that CpG methylation patterns of the human cyclin A1 promoter in human organs do not generally correlate with cyclin A1 gene expression in vivo.
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Ciclina A/genética , Metilación de ADN , Reacción en Cadena de la Polimerasa/métodos , Regiones Promotoras Genéticas , Colon/metabolismo , Islas de CpG/genética , Ciclina A1 , ADN Complementario/metabolismo , Células HeLa , Humanos , Intestino Delgado/metabolismo , Riñón/metabolismo , Masculino , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Bazo/metabolismo , Sulfitos/metabolismo , Testículo/metabolismo , Factores de Tiempo , Distribución Tisular , Células U937RESUMEN
The aim of this study was to determine whether the addition of whole body hyperthermia (WBH) to carboplatin (CBDCA) can induce responses in patients with platinum-resistant ovarian cancer. 16 pretreated patients with platinum-resistant ovarian cancer were entered on a Systemic Hyperthermia Oncological Working Group (SHOWG) study; (14 patients were eligible with 14 evaluable for toxicity and 12 for response). The patients were treated with WBH (Aquatherm) 41.8 degrees C x 60 min in combination with carboplatin (CBDCA) (area under the curve (AUC) of 8) every 4 weeks. Disease status was evaluated every two cycles. Patients were treated for a maximum of six cycles. One patient had a complete response (CR) and 4 had a partial response (PR). 4 patients had stable disease (SD). 3 patients had progressive disease (PD). 2 patients were unevaluable: 1 had a bowel obstruction shortly after her first treatment; the second patient achieved a CR, but only had one treatment secondary to an idiosyncratic reaction to sedative drugs. 2 patients entered on study were ineligible, as they did not meet criteria for platinum resistance; 1 entered a CR and 1 had SD. Dose-limiting toxicity, which required CBDCA dose reductions, was grade 4 thrombocytopenia. Other toxicities included neutropenia (grade 3/4), and nausea and/or vomiting. Consistent with preclinical modelling, these results suggests that 41.8 degrees C WBH can overcome platinum resistance in ovarian cancer. These observations suggest further investigation of the therapeutic potential of WBH in a group of patients who historically fail to respond to salvage therapies is warranted.
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Antineoplásicos/uso terapéutico , Carboplatino/uso terapéutico , Hipertermia Inducida/métodos , Neoplasias Ováricas/terapia , Adulto , Anciano , Antineoplásicos/efectos adversos , Carboplatino/efectos adversos , Terapia Combinada/métodos , Resistencia a Antineoplásicos , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Proyectos Piloto , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Results are described of a general health survey (n = 3044) that was conducted 6.5 years after the Chernobyl accident in 1986 in a seriously contaminated region in Belarus and a socioeconomically comparable, but unaffected, region in the Russian Federation. The purpose of the study was to investigate whether there are differences in the general health status of the inhabitants of the two regions that may be attributed to the Chernobyl disaster. A broad-based population sample from each of these regions was studied using a variety of self-report questionnaires. A subsample (n = 449) was further examined with a standardized physical and psychiatric examination. The results show significantly higher scores on the self-report questionnaires and higher medical service utilization in the exposed region. No significant differences were observed in global clinical indices of health. Although there were trends for some disorders to be more prevalent in the exposed region, none of these could be directly attributed to exposure to ionizing radiation. The results of this study suggest that the Chernobyl disaster had a significant long-term impact on psychological well-being, health-related quality of life, and illness behavior in the exposed population.
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Centrales Eléctricas , Traumatismos por Radiación/epidemiología , Traumatismos por Radiación/psicología , Liberación de Radiactividad Peligrosa/psicología , Adolescente , Adulto , Anciano , Exposición a Riesgos Ambientales , Femenino , Indicadores de Salud , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , República de Belarús/epidemiología , Federación de Rusia/epidemiología , UcraniaRESUMEN
PURPOSE: Bioactive lipids have been causally linked to intraabdominal malignancies such as ovarian cancer. In advanced tumors confined to the peritoneal cavity. inhibition of lipid growth factors present in ascites might induce tumor remissions. The systemic toxicity of the growth factor inhibitor suramin has so far hampered its use in standard oncologic practice, but this could be alleviated by intraperitoneal administration. In this study the feasibility, toxicity and pharmacokinetics of intraperitoneal suramin administration are described. METHODS: Patients with histologically verified cancer confined to the abdominal cavity, for which no effective therapy was available, were treated with intraperitoneal suramin through a Tenckhoff catheter. Patients with ascites were treated with low-volume continuous i.p. infusions of 500 mg/24 h, and patients without ascites were treated with intermittent large-volume i.p. infusions of 1000 mg three times a week. Regular pharmacokinetic sampling of plasma and ascites fluid was carried out. Patients were treated for 6 weeks or until development of progressive disease or until plasma suramin levels exceeded 250 mg/l. RESULTS: Nine patients were treated in ten periods, three with intermittent i.p. suramin, and seven with continuous i.p. suramin, for a median of 28.5 days (16-42 days), with a median suramin dose of 12 g (range 9 21 g ). Treatment was discontinued because of high systemic suramin levels in three patients (all in the intermittent schedule), progressive disease (five patients) or completion of planned treatment (one patient). Toxicity was mild, without any of the systemic side effects commonly associated with suramin. Intraperitoneal suramin levels were consistently higher than plasma levels in all patients, but this effect was most marked in the continuous infusion schedule. CONCLUSIONS: Intraperitoneal suramin infusion in patients with advanced peritoneal cancers is feasible and well-tolerated. Continuous low volume i.p. infusion in patients with ascites confers the largest pharmacokinetic advantage.
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Antineoplásicos/farmacocinética , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Mesotelioma/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Suramina/farmacocinética , Adulto , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Neoplasias de los Conductos Biliares/metabolismo , Conductos Biliares Intrahepáticos , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/metabolismo , Esquema de Medicación , Fatiga/inducido químicamente , Femenino , Humanos , Inyecciones Intraperitoneales , Lisofosfolípidos/metabolismo , Masculino , Mesotelioma/metabolismo , Persona de Mediana Edad , Neoplasias Ováricas/metabolismo , Neoplasias Peritoneales/metabolismo , Suramina/administración & dosificación , Suramina/uso terapéuticoRESUMEN
AIM: To predict the individual neonatal mortality risk of preterm infants using an artificial neural network "trained" on admission data. METHODS: A total of 890 preterm neonates (< 32 weeks gestational age and/or < 1500 g birthweight) were enrolled in our retrospective study. The neural network trained on infants born between 1990 and 1993. The predictive value was tested on infants born in the successive three years. RESULTS: The artificial neural network performed significantly better than a logistic regression model (area under the receiver operator curve 0.95 vs 0.92). Survival was associated with high morbidity if the predicted mortality risk was greater than 0.50. There were no preterm infants with a predicted mortality risk of greater than 0.80. The mortality risks of two non-survivors with birthweights > 2000 g and severe congenital disease had largely been underestimated. CONCLUSION: An artificial neural network trained on admission data can accurately predict the mortality risk for most preterm infants. However, the significant number of prediction failures renders it unsuitable for individual treatment decisions.
Asunto(s)
Mortalidad Infantil , Recien Nacido Prematuro , Recién Nacido de muy Bajo Peso , Redes Neurales de la Computación , Área Bajo la Curva , Femenino , Humanos , Recién Nacido , Modelos Logísticos , Masculino , Morbilidad , Estudios Retrospectivos , Medición de Riesgo , Sensibilidad y EspecificidadRESUMEN
Two female patients, aged 48 and 52 years, developed severe bone marrow suppression and (gastrointestinal) mucositis following administration of capecitabine. Analysis of the dihydropyrimidine dehydrogenase (DPD) activity in peripheral blood mononuclear cells revealed the presence of DPD deficiency. Both patients recovered in 3-4 weeks, and both had a (partial) remission of their tumours. Capecitabine is metabolised to 5-fluorouracil (5-FU) in the body. DPD-deficiency leads to impaired breakdown of 5-FU and hence to severe cytotoxicity following treatment with capecitabine or 5-FU. The most common mutation, IVS14 + 1G > A, is found in approximately 2% of the Dutch population. In case of unexpected severe toxicity during 5-FU or capecitabine treatment, DPD deficiency should be considered. Screening could be considered in view of the widespread use of capecitabine and 5-FU, the severe toxicity that may develop in patients with low DPD activity and the prevalence of the mutation.