Knowledge and management of traumatic dental injuries among schoolteachers in Hungary: a cross-sectional study with educational intervention.

PURPOSE: This study aimed to evaluate the knowledge of Hungarian schoolteachers in the management of dental trauma injuries (TDI) of children between the ages of 3 and 18 and to illustrate a brief educational intervention on TDI management. METHODS: A 15-item questionnaire on dental injuries was distributed in our observational cross-sectional study to 2720 Hungarian educational institutions to explore and evaluate teachers' knowledge in January 2019. Two years later, targeted information material was made accessible regarding TDI management. In the second post-intervention phase of the study, educator knowledge was re-evaluated using the same questionnaire. Statistical analysis (Mann-Whitney and Chi-square tests) was performed using IBM SPSS Statistics 28. RESULTS: A total of 1426 answers were collected in the initial survey. Although more than half (51.9%) of the respondents previously witnessed TDIs, 86.5% still did not perceive themselves as adequately informed regarding TDI management. Most teachers submitted appropriate responses to the indicator questions relating to the urgency of referral to dental professionals (71.8%), immediate contact with parents (79.0%) or dentists (13.0%), and the solution for avulsed teeth (81.3%). However, only every second (56.2%) educator responded correctly regarding the proper cleaning method. Following accessibility to our educational material, 622 respondents completed the post-intervention questionnaire in the second phase of the study. The percentage of appropriate responses to the five indicator questions significantly increased by 5-20.6%. CONCLUSION: Teachers' knowledge of TDI was inadequate yet can improve with online education. Efforts among dental professionals, the media, and targeted interventions will ensure adequate knowledge while also improving children's dental health.

Non-pain-related complaints of paediatric patients after dental treatment under general anaesthesia.

AIM: To investigate the prevalence, duration, and severity of non-pain-related complaints after dental treatment under general anaesthesia (DTGA) and to identify correlating factors from patient's characteristics and treatment. METHODS: Parents/caregivers of children treated under general anaesthesia were asked to fill in a dichotomous questionnaire during hospitalisation and the postoperative week. Several complaints were evaluated in relation to factors associated with dental treatment and general anaesthesia. CONCLUSION: Postoperative morbidity after DTGA is common. Patients and their parents should be informed about the possibility of experiencing mild to moderate complaints, and adverse events that may last up to 7 days.

Pain-related complaints of paediatric patients after dental treatment under general anaesthesia.

AIM: To identify factors related to postoperative pain and to recognise strategies to reduce this pain after dental treatment under general anaesthesia. METHODS: Cross-sectional observational study. Children treated under general ansesthesia reported pain daily using the Wong Baker FACES® Pain Rating Scale. Their parents/caregivers filled in a related Yes/No questionnaire during hospitalisation and the first postoperative week. The duration and severity of pain were evaluated in relation to various factors. CONCLUSION: A well-established protocol is indicated to reduce operation time. Patients and their parents should be informed about the possibility of constantly subsiding postoperative pain that may last for a week. As additional local anaesthesia during general anaesthesia (GA) does not provide postoperative pain reduction in deciduous tooth extraction cases, its administration could be omitted.

Structural and Morphometric Comparison of Lower Incisors in PACAP-Deficient and Wild-Type Mice.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with widespread distribution. PACAP plays an important role in the development of the nervous system, it has a trophic and protective effect, and it is also implicated in the regulation of various physiological functions. Teeth are originated from the mesenchyme of the neural crest and the ectoderm of the first branchial arch, suggesting similarities with the development of the nervous system. Earlier PACAP-immunoreactive fibers have been found in the odontoblastic and subodontoblastic layers of the dental pulp. Our previous examinations have shown that PACAP deficiency causes alterations in the morphology and structure of the developing molars of 7-day-old mice. In our present study, morphometric and structural comparison was performed on the incisors of 1-year-old wild-type and PACAP-deficient mice. Hard tissue density measurements and morphometric comparison were carried out on the mandibles and the lower incisors with micro-CT. For structural examination, Raman microscopy was applied on frontal thin sections of the mandible. With micro-CT morphometrical measurements, the size of the incisors and the relative volume of the pulp to dentin were significantly smaller in the PACAP-deficient group compared to the wild-type animals. The density of calcium hydroxyapatite in the dentin was reduced in the PACAP-deficient mice. No structural differences could be observed in the enamel with Raman microscopy. Significant differences were found in the dentin of PACAP-deficient mice with Raman microscopy, where increased carbonate/phosphate ratio indicates higher intracrystalline disordering. The evaluation of amide III bands in the dentin revealed higher structural diversity in wild-type mice. Based upon our present and previous results, it is obvious that PACAP plays an important role in tooth development with the regulation of morphogenesis, dentin, and enamel mineralization. Further studies are required to clarify the molecular background of the effects of PACAP on tooth development.

The NADPH oxidase NOX5 protects against apoptosis in ALK-positive anaplastic large-cell lymphoma cell lines.

Reactive oxygen species (ROS) are key modulators of apoptosis and carcinogenesis. One of the important sources of ROS is NADPH oxidases (NOXs). The isoform NOX5 is highly expressed in lymphoid tissues, but it has not been detected in any common Hodgkin or non-Hodgkin lymphoma cell lines. In diverse, nonlymphoid malignant cells NOX5 exerts an antiapoptotic effect. Apoptosis suppression is the hallmark feature of a rare type of lymphoma, termed anaplastic lymphoma kinase-positive (ALK(+)) anaplastic large-cell lymphoma (ALCL), and a major factor in the therapy resistance and relapse of ALK(+) ALCL tumors. We applied RT-PCR and Western blot analysis to detect NOX5 expression in three ALK(+) ALCL cell lines (Karpas-299, SR-786, SUP-M2). We investigated the role of NOX5 in apoptosis by small-interfering RNA (siRNA)-mediated gene silencing and chemical inhibition of NOX5 using FACS analysis and examining caspase 3 cleavage in Karpas-299 cells. We used immunohistochemistry to detect NOX5 in ALK(+) ALCL pediatric tumors. NOX5 mRNA was uniquely detected in ALK(+) ALCL cells, whereas cell lines of other lymphoma classes were devoid of NOX5. Transfection of NOX5-specific siRNA and chemical inhibition of NOX5 abrogated calcium-induced superoxide production and increased caspase 3-mediated apoptosis in Karpas-299 cells. Immunohistochemistry revealed focal NOX5 reactivity in pediatric ALK(+) ALCL tumor cells. These results indicate that NOX5-derived ROS contribute to apoptosis blockage in ALK(+) ALCL cell lines and suggest NOX5 as a potential pharmaceutical target to enhance apoptosis and thus to suppress tumor progression and prevent relapse in pediatric ALK(+) ALCL patients that resist classical therapeutic approaches.

Deficiency in the NADPH oxidase 4 predisposes towards diet-induced obesity.

OBJECTIVE: NADPH oxidase 4 (NOX4) is a reactive oxygen species (ROS) producing NADPH oxidase that regulates redox homeostasis in diverse insulin-sensitive cell types. In particular, NOX4-derived ROS is a key modulator of adipocyte differentiation and mediates insulin receptor signaling in mature adipocytes in vitro. Our study was aimed at investigating the role of NOX4 in adipose tissue differentiation, whole body metabolic homeostasis and insulin sensitivity in vivo. DESIGN: Mice with genetic ablation of NOX4 (NOX4-deficient mice) were subjected to chow or high-fat-containing diet for 12 weeks. Body weight gain, adiposity, insulin sensitivity, and adipose tissue and liver gene and protein expression were analyzed and compared with similarly treated wild-type mice. RESULTS: Here, we report that NOX4-deficient mice display latent adipose tissue accumulation and are susceptible to diet-induced obesity and early onset insulin resistance. Obesity results from accelerated adipocyte differentiation and hypertrophy, and an increase in whole body energy efficiency. Insulin resistance is associated with increased adipose tissue hypoxia, inflammation and adipocyte apoptosis. In the liver, more severe diet-induced steatosis was observed due to the lack of proper upregulation of mitochondrial fatty acid ß-oxidation. CONCLUSION: These findings identify NOX4 as a regulator of metabolic homeostasis. Moreover, they indicate an anti-adipogenic role for NOX4 in vivo and reveal its function as a protector against the development of diet-induced obesity, insulin resistance and hepatosteatosis.

High-throughput screening of saliva for early detection of oral cancer: a pilot study.

The success of tumour therapy depends considerably on early diagnosis. Therefore, we aimed to develop a widely available, cheap, non-invasive, high-throughput method suitable for screening high-risk populations, at least, for early signs of malignant transformation in the oral cavity. First, in order to identify suitable tumour marker candidates, we compared the protein patterns of five selected saliva samples obtained from healthy controls and tumour patients after electrophoretic separation, excised the bands that were consistently up-regulated in the tumour patients only, and performed matrix-assisted laser-desorption ionisation (MALDI)-time of flight (TOF) tandem mass spectrometry (MS/MS) analysis of the proteins in these bands after in-gel tryptic digestion. From the panel of proteins identified, we chose annexin 1 and peroxiredoxin 2 for further studies based on their presence in the saliva of all five oral cancer patients only. Then, we performed a homology search of protein databases using the primary sequence of each in silico tryptic fragment peptide of these two proteins as bait, and selected a unique peptide for each. Finally, we performed targeted MALDI-TOF MS peptide analysis in a blinded fashion on all samples obtained from 20 healthy controls and 22 tumour patients for the presence of these peptides. We found both peptides present in the saliva samples of all cancer patients only. Even though these tumour markers should be validated in a wider population, our results indicate that targeted MALDI-TOF MS analysis of unique peptides of putative saliva protein tumour biomarkers could be the method of choice for cost-efficient, high-throughput screening for the early detection of oral cancer.

Insulinemia and leptinemia in geriatric patients: markers of the metabolic syndrome or of undernutrition?

The metabolic syndrome (MS) describes a cluster of metabolic disturbances including type 2 diabetes and/or insulin resistance, hypertension, dyslipidemia and obesity, which predict a high risk of cardiovascular disorders. The associated hyperinsulinemia and hyperleptinemia may contribute to the cardiovascular risk. However, the operational value of the MS in elderly patients is questionable. We therefore investigated the prevalence and significance of the MS in geriatric care. In a survey of 98 consecutive admissions of diabetic patients, <40% had a MS; this is a low value compared to younger diabetic adults, due to a low prevalence of obesity and dyslipidemia. We found a high prevalence of low BMI (<20 kg/m2), hypoalbuminemia and low total cholesterol levels, suggesting that the MS may be modified by undernutrition. The interplay between the MS and undernutrition was further studied in 30 non-diabetic patients. Both leptinemia and insulin resistance indexes (HOMA-IR and QUICKI) were strongly associated with BMI and body fat (measured by Bioelectrical impedance Analysis). BMI, leptinemia and insulin resistance indexes were associated with the Mini Nutritional Assessment (MNA) score. Thus, undernutrition is associated with low leptin and insulin levels and may obscure the association of these parameters with cardiovascular risk. In conclusion, the MS has a low prevalence in our population of elderly diabetic patients, and is of questionable prognostic value. It can be oveshadowed by undernutrition, which is associated with low body weight, leptinemia and insulin resistance indexes. Prevention of undernutrition and/or adjustment to its consequences should receive higher priority in the care of elderly diabetic patients.

Expression of NOX1, a superoxide-generating NADPH oxidase, in colon cancer and inflammatory bowel disease.

Reactive oxygen species (ROS) are at the centre of many physiological and pathological processes. NOX1, a ROS-producing NADPH oxidase, is highly expressed in the colon but its function in colonic physiology or pathology is still poorly understood. It has been suggested to play a role in host defence, but also in cell growth and possibly malignant transformation. In this study we characterized NOX1 expression in human colon samples derived from healthy control subjects and patients with colon cancer or inflammatory bowel disease (IBD). NOX1 mRNA expression was assessed by dot-blot hybridization, real-time PCR and in situ hybridization, using samples derived from surgical specimens from patients undergoing colon resection. In normal tissues, NOX1 expression was low in the ileum, intermediate in the right colon, and high in the left colon (p = 0.0056 right vs. left colon). NOX1 mRNA levels were not influenced by factors linked to colon tumourigenesis, such as age or sex. Moreover, there was no statistical difference in NOX1 expression between samples derived from adenomas, well differentiated or poorly differentiated colon adenocarcinomas. At a cellular level, NOX1 was highly expressed in colon epithelial cells, both within the crypts and on the luminal surface. In addition, a population of lymphocytes, particularly in the appendix, showed NOX1 expression. Lymphocytes in lesions of Crohn's disease and ulcerative colitis were also strongly positive for NOX1. In conclusion, NOX1 is an enzyme that is constitutively expressed in colon epithelium and is not associated with tumourigenesis. Its distribution in crypts and on the luminal surface, as well as its left-to-right gradient in the colon, suggests a role in host defence function. In addition to the known epithelial localization, we define lymphocytes as a novel site of NOX1 expression, where it may potentially be involved in the pathogenesis of inflammatory bowel diseases.

Neuronal expression of the NADPH oxidase NOX4, and its regulation in mouse experimental brain ischemia.

Ischemia-induced neuronal damage has been linked to elevated production of reactive oxygen species (ROS) both in animal models and in humans. NADPH oxidase enzymes (NOX-es) are a major enzymatic source of ROS, but their role in brain ischemia has not yet been investigated. The present study was carried out to examine the expression of NOX4, one of the new NADPH oxidase isoforms in a mouse model of focal permanent brain ischemia. We demonstrate that NOX4 is expressed in neurons using in situ hybridization and immunohistochemistry. Ischemia, induced by middle cerebral artery occlusion resulted in a dramatic increase in cortical NOX4 expression. Elevated NOX4 mRNA levels were detectable as early as 24 h after the onset of ischemia and persisted throughout the 30 days of follow-up period, reaching a maximum between days 7 and 15. The early onset suggests neuronal reaction, while the peak period corresponds to the time of neoangiogenesis occurring mainly in the peri-infarct region. The occurrence of NOX4 in the new capillaries was confirmed by immunohistochemical staining. In summary, our paper reports the presence of the ROS producing NADPH oxidase NOX4 in neurons and demonstrates an upregulation of its expression under ischemic conditions. Moreover, a role for NOX4 in ischemia/hypoxia-induced angiogenesis is suggested by its prominent expression in newly formed capillaries.

Quantitative analysis of p53 expression and cell proliferation in gastric carcinomas. An immunohistochemical study.

BACKGROUND/AIMS: Adenocarcinoma of the stomach is still among the leading malignancies in human morbidity and mortality statistics in spite of endoscopic screening of the high-risk patients. Investigation of prognostic factors of gastric cancer disease seems to be still very important. The authors present a clinicopathological study based on the analysis of 49 gastric carcinomas. METHODOLOGY: P53 overexpression and proliferation activity of the cells were examined by immunohistological method with peroxidase-antiperoxidase technique. The percentage of the positive cells was calculated after counting of 300 tumor cells in each case. The rate of the labeled cells was related to different pathological characteristics of the carcinomas i.e., TNM stage of the tumor, histological subtypes of Ming's as well as Laurén's and Goseki's classification respectively, grade of differentiation and lymph node status. RESULTS: According to the above-mentioned parameters, p53 overexpression was significantly higher in carcinomas of the cardiac region than in those of the distal parts of the stomach. These findings are consistent with results published in the literature: cell proliferation rate alone is not an independent prognostic factor, but the degree of cell proliferation activity and p53 expression are changing usually parallel with each other and with other prognostic markers as well. CONCLUSIONS: The assessment of p53 activity and cell proliferation rate in gastric carcinoma is of prognostic value especially if evaluated together with other clinical and histopathological characteristics. The examination of these markers is useful in detecting early gastric cancer, in selecting high-risk patients and in planning proper individual treatment.

Expression of an alpha7 duplicate nicotinic acetylcholine receptor-related protein in human leukocytes.

We examined the potential expression and function of alpha7 nicotinic acetylcholine receptors (nAChRs) in leukocytes. RT-PCR with alpha7 specific primers revealed the presence of the receptor mRNA in leukocytes. Immunoblotting and immunofluorescence experiments demonstrated the expression of a protein that is recognized by alpha7 specific antibodies. However, nicotine and acetylcholine (ACh) failed to elicit current in leukocytes. Binding experiments with alpha-bungarotoxin rhodamine conjugated were negative, illustrating the absence of a high-affinity binding site. RT-PCR analysis revealed the selective expression of the dupalpha7 mRNA. These data indicate that leukocytes express in their membrane the dupalpha7 protein but its physiological role remains to be identified.

Esophageal intramural metastasis from adenocarcinoma of the gastroesophageal junction.

Among a total of 143 patients examined for diagnosis of adenocarcinoma of the cardia, intramural esophageal metastases were verified in six patients (4.19 %). In each case the diagnosis was confirmed by histological examination. The histological structure of the primary tumors and metastases was the same. Metastases were detected by endoscopic ultrasound examination in three cases. All the cardia tumors proved to be well advanced. As well as endoscopic identification of the primary tumor, thorough examination of the proximal part of the esophagus is of great importance.

[What kind of surgical radicality is justified in the treatment of esophageal and cardial carcinoma?]. / Wie radikal soll das Osophagus- bzw. Kardiakarzinom operiert werden?

In the period from January 1, 1973 to November 30, 1994, a total number of 1 856 patients had been admitted to our Department of Surgery because of cancer of the esophagus and esophago-gastric junction. We divided our activities into two study periods. In the first study period from 1973 to 1984 only so called "conventional operations" were performed. Since 1985 new oncological aspects were introduced into our operative tactics:1. the subtotal esophagectomy combined with the two-field lymphadenectomy,2. the total gastrectomy with extended lymph node dissection. The analysis of our results with respect to the survival parameters (TNM staging, histological type, grade of differentiation, gross pathology) showed that the best chances were obtained by curative resection and lymphadenectomy in tumours of low-grade biologic malignancy. In esophageal cancers the former 6 % 5-year cumulative survival rate increased to 26 %, and in cardia tumours from 9 to 27 %, because of enhancement of radicality and extension of lymphadenectomy.

[Esophageal anastomosis--based on the experience with 1460 operations]. / Nyelócsó anasztomózisokról: 1460 mútét tapasztalata alapján.

The authors reviewed the clinical records of 1460 patients with esophageal anastomoses, the operations performed in their institute between 1973 and 2000. Surgical outcome was assessed with incidence of anastomotic leaks and overall mortality. Hand-sewn anastomoses were performed by inserting single layer interrupted monofil steel wire (507), PDS (232) or Vicryl (65) sutures and circular stapler (EEA, Ethicon) was used in 656 patients. 453 (65 cervical, 293 thoracic, and 95 abdominal) anastomoses performed between 1995 and 2000 were analyzed separately. During this 6-year period, the majority of operations (88%) were performed because of esophageal malignancy (squamous cell carcinoma of the esophagus or adenocarcinoma of the cardia). Surgery was performed for benign disease (e.g. stricture, perforation, and stage IV achalasia) in 12%. The incidence of anastomotic leak was the highest (20%) after cervical anastomosis, compared to a 4.4% or 1% associated with thoracic or abdominal anastomoses. These differences are statistically significant (p < 0.001). The rate of anastomotic leakage was strongly connected to surgical technique: it was 15% in hand-sewn anastomoses and only 4.4% with stapled anastomosis. During the 6-year period overall mortality was 6.6%t.

[Siewert-Stein classification of adenocarcinoma of the esophagogastric junction]. / Az oesophagogastricus junctio adenocarcinomáinak Siewert-Stein klasszifikációjáról.

Nowadays the terminology used for the definition of adenocarcinomas at the oesophagogastric junction is "cardiac carcinoma", which can be easily misunderstood. This definition of adenocarcinomas of the oesophagogastric junction does not allow correct comparison of diagnosis (endoscopic, radiological and pathologic), epidemiology and surgical therapy in national and international aspects, because different tumours can develope in the same area, and all called cardia tumors. Siewert and Stein recommended a classification to solve this problem. The classification of the tumours is morphological/topographical. Type I is adenocarcinoma of the distal part of the oesophagus. Type II is adenocarcinoma of the real cardia and type III is subcardial gastric adenocarcinoma. At classification, we always consider results of endoscopy (ortograde and retroflexed view of the oesophago-gastric junction), the x-rays of the oesophagus and stomach, findings at the operation and pathohistologic results. Between 1/1/1974 and 31/12/2000, a total number of 50,878 upper panendoscopic examinations were performed at the Endoscopic Laboratory of the Surgical Department. Adenocarcinoma of the cardia was diagnosed in 488 patients. According to the Siewert-Stein classification, type I tumour was found in 123 (25.2%), type II in 240 (49.18%), and type III was present in 125 (25.61%) patients. The importance of this classification is it enables unified pre-operative assessment and it can also help to decide the type of the surgical intervention. In our patients with type I cancer--depending of the size of the tumour--distal 2/3 oesophagectomy with the resection of the proximal lesser curve of the stomach or total gastrectomy were performed. In the first group oesophago-jejuno-gastrostomy, in case of total gastrectomy Roux-en-Y loop anastomosis was created. In patients with types II and III cancers total gastrectomy was performed. In every patient lymphadenectomy was performed. We suggest the use of this new classification in clinical, gastroenterology--with special regard to the endoscopy--and pathology.

[Perspectives of laparoscopy in cardia and gastric surgery]. / A laparoszkópia útkeresése a cardiatáj és a gyomor sebészetében.

The authors have made 171 laparoscopic operations in the gastro-esophageal region during the past three and a half years. They have used the achievement of the minimal invasive surgery mainly in the treatment of functional diseases of the gastro-esophageal junction. Besides the hiatal reconstruction and antireflux procedures (142), endoscopic assisted cysto-gastrostomy (7), endoscopic assisted double-lifting gastric wall resection (5), cardiomyotomy (4), Graham suture of perforated duodenal ulcer (4) and enucleation of gastric wall leiomyoma (2) has been performed. There was no postoperative death, the rate of conversion was altogether 4.7% (8/171) while there was no need for reoperation in the early postoperative period.

[Endoscopic diagnosis of gastrointestinal bleeding of unknown origin]. / Az ismeretlen eredetú gasztrointesztinális vérzések enteroszkópos diagnosztikája.

In recent years push enteroscopy has become the most important method in the examination of patients with obscure gastrointestinal bleeding. We summarise our experiences with 148 enteroscopies performed on 140 patients with bleeding of unknown origin. The source of bleeding could be identified in 81 patients (57.86%). The most common lesions were small bowel tumors (13.57%) and vascular malformations (12.86%). Several patients (22.86%) referred for enteroscopy had lesions in the esophagus, stomach and proximal duodenum that were missed at upper endoscopy. The authors conclude that push enteroscopy has a major role in the evaluation of patients with obscure gastrointestinal bleeding. Enteroscopy should be the first diagnostic step after negative esophago-gastroduodenoscopy and negative colonoscopy. Enteroscopy seems to be superior to other diagnostic methods. It is well tolerable and is not time consuming.

[Rare late complication after subtotal esophagectomy]. / Nyelócsórezekció után kialakult ritka késói szövódmény.

We report a case of a peptic ulcer developed in the stomach tube used for the replacement of the esophagus. The patient was a 60 years old female who had undergone subtotal esophagectomy for mid esophageal malignancy, with intrapleural stomach replacement. Urgent endoscopy revealed an excavated, bleeding ulcer in the thoracic part of the stomach. After unsuccessful medical treatment urgent operation was performed via right thoracotomy. Opening the stomach an ulcer was found on the posterior wall of the stomach, it was penetrating to the right atrium of the heart. The bleeding was controlled by suturing the atrium wall. The patient treated with i.v. Omeprazol in the postoperative period. On the 21st postoperative day a rebleeding occurred causing shock. After reoperation the patient died. This complication is very rare. We emphasise the importance of postoperative pH measurement investigations showing the presence of duodenogastric reflux disease.

Phase I/II trial of the multidrug-resistance modulator valspodar combined with cisplatin and doxorubicin in refractory ovarian cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of doxorubicin when given in combination with cisplatin and the multidrug-resistance (MDR) modulator valspodar and the remission rate induced by this combination in patients with platinum- and anthracycline-resistant ovarian cancer. PATIENTS AND METHODS: Fifty-nine patients who had failed prior platinum- and anthracycline-based chemotherapy were enrolled. During the dose-finding phase, patients received a loading dose of valspodar (1.5 or 2 mg/kg) via 2-hour intravenous (IV) infusion on day 1 and continuous IV infusion (CIVI) of valspodar (2, 4, or 10 mg/kg/d) over 3 days. Doxorubicin (starting from 20 up to 50 mg/m(2)) and cisplatin (50 mg/m(2)) were administered via 15- to 20-minute IV infusions on day 3. During the efficacy phase, patients received at least two treatment cycles unless toxicity was unacceptable, and responding patients and those with stable disease received four to six cycles. RESULTS: All patients completed at least one cycle of combined treatment. The MTD of doxorubicin was determined to be 35 mg/m(2) when administered with valspodar at 2 mg/kg loading dose and 10 mg/kg/d CIVI plus 50 mg/m(2) cisplatin. At these doses, valspodar blood concentrations known to reverse MDR in vitro were reached in all patients. Valspodar was well tolerated at all dose levels. Dose-limiting toxicities of the combination were primarily hematologic and included febrile neutropenia and prolonged leucopenia. The addition of valspodar to the treatment did not worsen cisplatin-related toxicity. Among 33 patients treated at the MTD for doxorubicin, one (3%) had a complete response, and four (12%) had a partial response. An additional seven patients experienced a stabilization of their previously progressive disease. The survival rates at 6 and 12 months were 59% and 19%, respectively. CONCLUSION: Valspodar can be safely coadministered with doxorubicin and cisplatin. Although the regimen used in this trial produced renewed responses in patients with heavily pretreated, refractory ovarian cancer, the value of valspodar in reversing resistance mediated by P-glycoprotein remains to be determined.