Postoperative outcomes of primary and interval cytoreductive surgery for advanced ovarian cancer registered in the Dutch Gynecological Oncology Audit (DGOA).

OBJECTIVES: The challenge when performing cytoreductive surgery (CRS) is to balance the benefits and risks. The aim of this study was to report short term postoperative morbidity and mortality in relation to surgical outcome in patients undergoing primary debulking surgery (PDS) or interval debulking (IDS) surgery in the Netherlands. METHODS: The Dutch Gynecological Oncology Audit (DGOA) was used for retrospective analysis. Patients undergoing PDS or IDS between January 1st, 2015 - December 31st, 2018 were included. Outcome was frequency of postoperative complications. Median time to adjuvant chemotherapy and severity of complications were related to outcome of CRS. Complications with Clavien-Dindo ≥3 were analyzed per region and case mix corrected. Statistical analysis was performed with R.Studio. RESULTS: 1027 patients with PDS and 1355 patients with IDS were included. Complications with re-invention were significantly higher in PDS compared to IDS (5.7% vs. 3.6%, p = 0.048). Complete cytoreduction was 69.7% in PDS and 62.1% IDS, p < 0.001. Time to adjuvant chemotherapy was 49 days in patients with complete CRS and a complication with re-intervention. Regional variation for severe complications showed one region outside confidence intervals. CONCLUSIONS: Higher complete cytoreduction rate in the PDS group indicates that the correct patients have been selected, but is associated with a higher percentage of complication with re-intervention. As result, time to start adjuvant chemotherapy is longer in this group. Maintaining a balance in aggressiveness of surgery and outcome of the surgical procedure with respect to severe complications is underlined. Bench marked data should be discussed nationally to improve this balance.

No influence of sarcopenia on survival of ovarian cancer patients in a prospective validation study.

OBJECTIVE: Decrease in skeletal muscle index (SMI) during neoadjuvant chemotherapy (NACT) has been associated with worse outcome in patients with advanced ovarian cancer. To validate these findings, we tested if a decrease in SMI was a prognostic factor for a homogenous cohort of patients who received NACT in the randomized phase 3 OVHIPEC-trial. METHODS: CT-scans were performed at baseline and after two cycles of neoadjuvant chemotherapy in stage III ovarian cancer patients. The SMI (skeletal muscle area in cm2 divided by body surface area in m2) was calculated using SliceOMatic software. The difference in SMI between both CT-scans (ΔSMI) was calculated. Cox-regression analyses were performed to analyze the independent effect of a difference in SMI (ΔSMI) on outcome. Log-rank tests were performed to plot recurrence-free (RFS) and overall survival (OS). The mean number of adverse events per patient were compared between groups using t-tests. RESULTS: Paired CT-scans were available for 212 out of 245 patients (87%). Thirty-four of 74 patients (58%) in the group with a decrease in ΔSMI and 73 of 138 of the patients (53%) in the group with stable/increase in ΔSMI had died. Median RFS and OS did not differ significantly (p = 0.297 and p = 0.764) between groups. Patients with a decrease in SMI experienced more pre-operative adverse events, and more grade 3-4 adverse events. CONCLUSION: Decreased SMI during neoadjuvant chemotherapy was not associated with worse outcome in patients with stage III ovarian cancer included in the OVHIPEC-trial. However, a strong association between decreasing SMI and adverse events was found.

[Treatment evaluation and clinical decision making using HKT-30-ROM]. / Behandelevaluatie en klinische besluitvorming met HKT-30-ROM.

BACKGROUND: By means of repeated, well-supported measurements of clinical dynamic indicators from the Historical, Clinical and Future - 30 (HKT-30) it is possible to monitor behavioural changes on the basis of risks and needs. The addition of extra score parameters allows us to distinguish client-specific risks and needs. In treatment evaluation it is important to visualise changes in these indicators of treatment evaluation because they are the key to the clinical decision-making process that determines further treatment and rehabilitation. AIM: To investigate whether HKT-30 indicators can be used to measure and visualise behavioral changes for the purpose of treatment evaluation. METHOD: A case study is used to illustrate how clinicians at the Forensic Psychiatric Clinic (FPK), De Woenselse Poort, ascertain risks, needs and changes and clarify these factors for the purpose of treatment evaluation and clinical decision-making. RESULTS: Routine treatment evaluation aided by visualised clinical HKT-30 indicators give the treatment team and the client a clearer picture of the behavioral changes for which the forensic treatment was prescribed. This evaluation provides significant starting-points for clinical decision making. CONCLUSION: Routine treatment evaluation along with a suitably adjusted HKT-30 make behavioural changes visible, render clinical decisions more transparent and provide valuable starting-points for a dialogue with the client about his treatment.

An overview of Clinical Quality Registries (CQRs) on gynecological oncology worldwide.

INTRODUCTION: Clinical Quality Registries (CQRs) were initiated in order to compare clinical outcomes between hospitals or regions within a country. To get an overview of these CQRs worldwide the aim of this study was to identify these CQRs for gynecological oncology and to summarize their characteristics, processes and QI's and to establish whether it is feasible to make an international comparison in the future. METHODS: To identify CQRs in gynecological oncology a literature search in Pubmed was performed. All papers describing the use of a CQR were included. Administrative, epidemiological and cancer registries were excluded as these registries do not primarily serve to measure quality of care through QI's. The taskforce or contact person of the included CQR were asked to participate and share information on registered items, processes and indicators. RESULTS: Five nations agreed to collaborate: Australia, Denmark, Italy, the Netherlands and Sweden. Denmark, Netherlands and Sweden established a nationwide registry, collecting data on multiple tumor types, and various QI's. Australia and Italy included patients with ovarian cancer only. All nations had a different process to report feedback results to participating hospitals. CONCLUSION: CQRs serve the same purpose to improve quality of care but vary on different aspects. Although similarities are observed in the topics measured by the QI's, an international comparison was not feasible as numerators or denominators differ between registries. In order to compare on an international level it would be useful to harmonize these registries and to set an international standard to measure the quality of care with similar indicators.

Clinical auditing as an instrument to improve care for patients with ovarian cancer: The Dutch Gynecological Oncology Audit (DGOA).

INTRODUCTION: The Dutch Gynecological Oncology Audit (DGOA) was initiated in 2014 to serve as a nationwide audit, which registers the four most prevalent gynecological malignancies. This study presents the first results of clinical auditing for ovarian cancer in the Netherlands. METHODS: The Dutch Gynecological Oncology Audit is facilitated by the Dutch Institute of Clinical Auditing (DICA) and run by a scientific committee. Items are collected through a web-based registration based on a set of predefined quality indicators. Results of quality indicators are shown, and benchmarked information is given back to the user. Data verification was done in 2016. RESULTS: Between January 01, 2014 and December 31, 2018, 6535 patients with ovarian cancer were registered. The case ascertainment was 98.3% in 2016. The number of patients with ovarian cancer who start therapy within 28 days decreased over time from 68.7% in 2014 to 62.7% in 2018 (p < 0.001). The percentage of patients with primary cytoreductive surgery decreased over time (57.8%-39.7%, P < 0.001). However, patients with complete primary cytoreductive surgery improved over time (53.5%-69.1%, P < 0.001). Other quality indicators did not significantly change over time. CONCLUSION: The Dutch Gynecological Oncology Audit provides valuable data on the quality of care on patients with ovarian cancer in the Netherlands. Data show variation between hospitals with regard to pre-determined quality indicators. Results of 'best practices' will be shared with all participants of the clinical audit with the aim of improving quality of care nationwide.

Health-related quality of life after interval cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with stage III ovarian cancer.

INTRODUCTION: The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery (CRS) improves recurrence-free (RFS) and overall survival (OS) in patients with FIGO stage III ovarian cancer. We evaluated the effect of HIPEC on patient's health-related quality of life (HRQoL) in the OVHIPEC trial. MATERIALS AND METHODS: OVHIPEC was a multicentre, open-label, randomized phase III trial for patients with stage III ovarian cancer. Patients were randomly assigned (1:1) to receive interval CRS with or without HIPEC with cisplatin. HRQoL was assessed using the EORTC QLQ-C30, and the ovarian (QLQ-OV28) and colorectal cancer (QLQ-CR38) modules. HRQoL questionnaires were administered at baseline, after surgery, after end of treatment, and every three months thereafter. HRQoL was a secondary endpoint, with the prespecified focus on the QLQ-C30 summary score and symptom scores on fatigue, neuropathy and gastro-intestinal symptoms. HRQoL was analysed using linear and non-linear mixed effect models. RESULTS: In total, 245 patients were randomized. One-hundred-ninety-seven patients (80%) completed at least one questionnaire. No significant difference over time in the QLQ-C30 summary scores was observed between the study arms (p-values for linear and non-linear growth: p > 0.133). The pattern over time for fatigue, neuropathy and gastro-intestinal symptoms did not significantly differ between treatment arms. CONCLUSION: The addition of HIPEC to interval CRS does not negatively impact HRQoL in patients with stage III ovarian cancer who are treated with interval CRS due to the extent of disease. These HRQoL results, together with the improvement in RFS and OS, support the viability of HIPEC as an important treatment option in this patient population. CLINICALTRIALS. GOV NUMBER: NCT00426257. EUDRACT NUMBER: 2006-003466-34.

Modulation of the major histocompatibility complex class II-associated peptide repertoire by human histocompatibility leukocyte antigen (HLA)-DO.

Antigen presentation by major histocompatibility complex class II molecules is essential for antibody production and T cell activation. For most class II alleles, peptide binding depends on the catalytic action of human histocompatibility leukocyte antigens (HLA)-DM. HLA-DO is selectively expressed in B cells and impedes the activity of DM, yet its physiological role remains unclear. Cell surface iodination assays and mass spectrometry of major histocompatibility complex class II-eluted peptides show that DO affects the antigenic peptide repertoire of class II. DO generates both quantitative and qualitative differences, and inhibits presentation of large-sized peptides. DO function was investigated under various pH conditions in in vitro peptide exchange assays and in antigen presentation assays using DO(-) and DO(+) transfectant cell lines as antigen-presenting cells, in which effective acidification of the endocytic pathway was prevented with bafilomycin A(1), an inhibitor of vacuolar ATPases. DO effectively inhibits antigen presentation of peptides that are loaded onto class II in endosomal compartments that are not very acidic. Thus, DO appears to be a unique, cell type-specific modulator mastering the class II-mediated immune response induced by B cells. DO may serve to increase the threshold for nonspecific B cell activation, restricting class II-peptide binding to late endosomal compartments, thereby affecting the peptide repertoire.

Activated complement is more extensively present in diseased aortic valves than naturally occurring complement inhibitors: a sign of ongoing inflammation.

BACKGROUND: Recent studies indicate a role for complement in the pathogenesis of aortic valve disease. However, the role of naturally occurring anti-complement mediators in this context is unknown. In this study, we have analysed this in three different pathological conditions of the aortic valve: degeneration, atherosclerosis and bacterial endocarditis. MATERIALS AND METHODS: Human aortic valves were obtained at autopsy (n = 30): 5 control valves, 10 aortic valves with atherosclerotic changes, 10 aortic valves with degenerative changes and 5 degenerative changed aortic valves with bacterial infection. These valves were analysed immunohistochemically for the presence of activated complement (C3d and C5b9) and the complement inhibitors C1-inh and clusterin. Areas of positivity were then quantified. RESULTS: C3d, C5b9 and the complement inhibitors C1-inh and clusterin depositions were mainly found in the endothelium and extracellular matrix in aortic valves. All these mediators were already present in control valves, but the area of positivity increased significantly in response to the different diseases, with the highest increase in response to bacterial endocarditis. Interestingly, in all three aortic diseases, the depositions of complement were significantly more widespread than that of their inhibitors. CONCLUSIONS: Our study indicates that anti-complement mediators (C1-inh and clusterin) are deposited in diseased aortic valves together with activated complement, indicating an existing counter response against complement locally in the valve. However, deposition of activated complement is significantly more widespread than that of its inhibitors, which could explain ongoing inflammation in those diseased aortic valves.

Comparison of GP5+/6+-PCR and SPF10-line blot assays for detection of high-risk human papillomavirus in samples from women with normal cytology results who develop grade 3 cervical intraepithelial neoplasia.

Using a case control approach, we performed a two-way comparison study between GP5+/6+-PCR and HPV SPF(10)-Line Blot 25 (SPF(10)) assays for detection of 14 types of high-risk human papillomavirus (hrHPV) in samples from women with normal cytology results who had or developed grade 3 cervical intraepithelial neoplasia (CIN 3). Samples were pooled from two cohorts, i.e., women participating in population-based screening and women attending a gynecological outpatient clinic. Cases (n = 45) were women with histologically confirmed CIN 3 diagnosed within a median follow-up time of 2.7 (range, 0.2 to 7.9) years. Control samples were from women (n = 264) who had developed CIN 1 lesions at maximum (median follow-up at 5.8 [range, 0 to 10] years). Identical numbers of cases tested positive for 1 or more of the 14 hrHPV types by both systems (40/45; McNemar; P = 1.0). Conversely, SPF(10) scored significantly more controls as hrHPV positive than did GP5+/6+-PCR (95/264 versus 29/264; McNemar; P < 0.001). Consequently, women with normal cytology results and an hrHPV GP5+/6+-PCR-positive test exhibited a risk of CIN 3 that was 4.5 times higher (odds ratio [OR], 65; 95% confidence interval [95%CI], 24 to 178) than that seen for women with an hrHPV-positive SPF(10) test (OR, 14; 95%CI, 5 to 38)). Similar results were obtained after analysis of both cohorts separately. Discrepancy analysis by viral load assessment for the most common discordant hrHPV types (HPV16, -18, and -52) showed that samples which were SPF(10) positive only for these types had viral loads significantly lower than those for samples that were positive by both assays (analysis of variance; P < or = 0.006). Our data indicate that GP5+/6+-PCR has a better clinical performance than SPF(10) for women who are diagnosed with CIN 3 after prior normal cytology results. The extra positivity scored by SPF(10) mainly involved infections characterized by low viral loads that do not result in CIN 3.

First case of vaginal radical trachelectomy in a pregnant patient.

Women who present with cervical carcinoma during pregnancy pose for us a clinical problem. In general, three treatment options exist: (i) radical hysterectomy with termination of pregnancy, (ii) a planned delay, or (iii) chemotherapy until lung maturation has occurred, both followed by a radical hysterectomy. Vaginal radical trachelectomy is an alternative approach to preserve the pregnancy. We report on a woman with a stage IBI cervical carcinoma, diagnosed at 16 weeks of gestation treated with vaginal radical trachelectomy. At a gestational age of 36 weeks, a cesarean section was performed, followed by radical hysterectomy. Follow-up of 9 months is uneventful for both the mother and the child. The vaginal radical trachelectomy is a new approach in the treatment of cervical carcinoma during pregnancy.

The zyxin-related protein TRIP6 interacts with PDZ motifs in the adaptor protein RIL and the protein tyrosine phosphatase PTP-BL.

The small adaptor protein RIL consists of two segments, the C-terminal LIM and the N-terminal PDZ domain, which mediate multiple protein-protein interactions. The RIL LIM domain can interact with PDZ domains in the protein tyrosine phosphatase PTP-BL and with the PDZ domain of RIL itself. Here, we describe and characterise the interaction of the RIL PDZ domain with the zyxin-related protein TRIP6, a protein containing three C-terminal LIM domains. The second LIM domain in TRIP6 is sufficient for a strong interaction with RIL. A weaker interaction with the third LIM domain in TRIP6, including the proper C-terminus, is also evident. TRIP6 also interacts with the second out of five PDZ motifs in PTP-BL. For this interaction to occur both the third LIM domain and the proper C-terminus are necessary. RNA expression analysis revealed overlapping patterns of expression for TRIP6, RIL and PTP-BL, most notably in tissues of epithelial origin. Furthermore, in transfected epithelial cells TRIP6 can be co-precipitated with RIL and PTP-BL PDZ polypeptides, and a co-localisation of TRIP6 and RIL with Factin structures is evident. Taken together, PTP-BL, RIL and TRIP6 may function as components of multi-protein complexes at actin-based sub-cellular structures.

Identification and molecular characterization of BP75, a novel bromodomain-containing protein.

We here describe the identification and characterization of a novel bromodomain-containing protein, the bromodomain protein of 75 kDa (BP75). Initially, we identified BP75 in a two-hybrid screening for proteins that interact with the first PDZ (acronym for post-synaptic density protein PSD-95, Drosophila discs large tumor suppressor DlgA and the tight junction protein ZO-1) domain in protein tyrosine phosphatase-BAS-like (PTP-BL). We found that BP75 is expressed ubiquitously and show that both BP75 and a PTP-BL deletion mutant consisting of the first PDZ domain are located mainly in the nucleus, although cytoplasmic localization is also evident. Full-length PTP-BL, on the contrary, is predominantly localized in the cytoplasm, although some basal nuclear staining is observed. The described molecular interaction may reflect a mechanism of coupling submembraneous signalling events and nuclear events.

Maternal consequences of caesarean section. A retrospective study of intra-operative and postoperative maternal complications of caesarean section during a 10-year period.

OBJECTIVES: This study was performed to assess the intra-operative surgical complications and postoperative maternal morbidity rate of caesarean section. STUDY DESIGN: A total of 2647 women, delivered by caesarean section in our department between 1983 and 1992, were studied retrospectively. Three caesarean section groups were formed: (1) primary elective, (2) primary acute, without any effort to deliver vaginally, and (3) secondary acute, due to a failed vaginal delivery. The Student's-t-, Fisher-exact- and chi 2-test were used for statistical analysis. RESULTS: The overall maternal intra-operative complication rate was 14.8%. The most common complications were lacerations of the uterine corpus (10.1%) and bloodloss > or = 1000 ml (7.3%). The complication rate of the secondary group (23.4%) was significantly higher (p < 0.001) compared to both primary groups (7.4%). The overall maternal postoperative morbidity rate was 35.7%. Fever (24.6%), bloodloss between 1000 and 1500 ml (4%), haematoma (3.5%) and urinary tract infections (3.0%) were the most frequent complications. The primary elective group showed significantly (p < 0.001) lower major (2.6%) and minor (23.7%) complication rates compared to the emergency groups (major 5.2%, minor 34%). CONCLUSION: Emergency caesarean sections carried the greatest risks regarding maternal complications compared to elective procedures.

Predicting the risk of bluetongue through time: climate models of temporal patterns of outbreaks in Israel.

Determining the temporal relationship between climate and epidemics of Culicoides-borne viral disease may allow control and surveillance measures to be implemented earlier and more efficiently. In Israel, outbreaks of bluetongue (BT) have occurred almost annually since at least 1950, with severe episodes occurring periodically. In this paper, the authors model a twenty-year time-series of BT outbreaks in relation to climate. Satellite-derived correlates of low temperatures and high moisture levels increased the number of outbreaks per year. This is the first study to find a temporal relationship between the risk of Culicoides-borne disease and satellite-derived climate variables. Climatic conditions in the year preceding a BT episode, between October and December, coincident with the seasonal peak of vector abundance and outbreak numbers, appeared to be more importantthan spring or early summer conditions in the same year as the episode. Since Israel is an arid country, higher-than-average moisture levels during this period may increase the availability of breeding sites and refuges for adult Culicoides imicola vectors, while cooler-than-average temperatures will increase fecundity, offspring size and survival through adulthood in winter, which, in turn, increases the size of the initial vector population the following year. The proportion of variance in the annual BT outbreak time-series resulting from climate factors was relatively low, at around 20%. This was possibly due to temporal variation in other factors, such as viral incursions from surrounding countries and levels of herd immunity. Alternatively, since most BT virus (BTV) circulation in this region occurs silently, in resistant breeds of local sheep, the level of transmission is poorly correlated with outbreak notification so that strong relationships between BTV circulation and climate, if they exist, are obscured.

Organisation and functions of class II genes and molecules.

The class II region of the human MHC contains all of the known class II genes: as well as antigen processing components and only one gene not obviously associated with the immune system, RING3. As an approach to understanding linkage disequilibrium and recombination in relation to polymorphism of the region we are cloning and sequencing the class II region. To date, the sequence of the DP-DQ region has almost been completed (see Report by S. Beck). Several sets of genes implicated in the immune system, especially in antigen processing and presentation, are clustered together in the MHC: class I (HLA-A, B, C etc) class II (DR, DQ, DP, DN, DO, DM) LMP2 and 7, TAP1 and 2, TNF, C2, C4, Bf, Hsp70. This situation has provoked speculation that the MHC behaves as a gene cluster in which allelic products of polymorphic genes are maintained on a haplotype so as to co-ordinate T cell repertoire development and deployment. The high levels of linkage disequilibrium across the region are consistent with this idea. Functions of the genes in the MHC are being investigated as a step towards gaining insight into antigen processing and presentation as well as understanding MHC-disease associations. We are concentrating on the functions of the class II-related genes, DM and DN/DO as well as the TAP/LMP cluster.

Corynebacterium pseudotuberculosis infection in Israeli cattle: clinical and epidemiological studies.

Morbidity due to Corynebacterium pseudotuberculosis infection occurred in 29 dairy herds in Israel during 1989 to 1995. The disease occurred sporadically in 17 of the herds with a morbidity of up to 5 per cent, and was epidemic in 12, with a morbidity of 5 to 35 per cent. Cutaneous abscesses were diagnosed in 609 animals. Young cattle appeared to be less susceptible to the disease than older cows. Beef cattle herds were not affected. The disease appeared in the cutaneous form in 92.5 per cent of cases, the cutaneous and mastitic form in 5.9 per cent and the cutaneous and visceral form in 1.6 per cent. The cutaneous form appeared as deep subcutaneous abscesses on various parts of the body, with granulating ulcers exuding pus and blood. In 10 of the herds, C pseudotuberculosis was isolated from 33 mastitic cows which also had cutaneous lesions. The visceral form of the disease was detected when severely affected animals were slaughtered. In 23 of the herds, the disease occurred during the spring and summer dry season, from March to October; the highest prevalence was in the semi-arid Negev region. In 25 herds, the infection lasted for up to five months. The skin lesions on individual cows healed on average in 23.4 days, after either local or parenteral treatment. No significant difference was observed between the effect of systemic antibiotic treatment and local antiseptic treatment. One hundred and two (16.7 per cent) severely affected animals were culled. There was a decrease in milk production and large increases in somatic cell counts in the 12 herds in which the disease was epidemic. None of the strains of isolated C pseudotuberculosis reduced nitrate.

Epidemiological investigations of outbreaks of bovine ephemeral fever in Israel.

In two epidemics of bovine ephemeral fever (BEF) in Israel, one in 1990 and one in 1999, the virus was probably carried by vectors transported by air currents across the Rift Valley and through the Red Sea trough. The disease broke out under optimal ecological conditions among vulnerable cattle populations and spread rapidly; it developed in the spring and summer and ended soon after the daily average ambient temperature fell below 16 degrees C in late autumn. The proportion of herds affected reached 78.4 and 97.7 per cent in 1990 and 1999, respectively. The highest rates of incidence, morbidity and mortality were recorded in dairy cattle herds in the Jordan Valley, the initial focus of the outbreaks, with a morbidity of 20 and 38.6 per cent in 1990 and 1999, respectively, and mortality among the affected animals of 2 and 8.6 per cent in 1990 and 1999, respectively. In 1991, the disease recurred sporadically in the central and southern regions of Israel in only three herds, but in 2000 the disease returned on an epidemic scale, and 85 per cent of herds were affected, with morbidity and mortality rates of 4-3 and 0-3 per cent, respectively. In the 1999 epidemic, the morbidity rate decreased from 38-6 per cent on average in the Jordan Valley to 12.8 per cent in the inner valleys and 5.3 per cent on the Mediterranean coastal plain, but the mortality rate increased from 8-6 per cent in the Jordan Valley to 14-3 per cent in the inner valleys, and to 28 per cent on the Mediterranean coastal plain, where the outbreak declined. An average of 2-7 per cent of the animals experienced a second attack of the disease two to six weeks later. The epidemic in 2000 was milder and shorter than that in 1999. All the cattle affected in both outbreaks were more than three months old. The vector(s) is not known for certain but the available evidence indicates that mosquitoes, and not Culicoides species, are the natural vectors of BEF virus in Israel.

Cardiomyopathy in cattle induced by residues of the coccidiostat maduramicin in poultry litter given as a feedstuff.

An experimental feeding trial was conducted in order to substantiate an hypothesis on the aetiology of a previously unrecorded cardiomyopathic syndrome in beef cattle in Israel. It was believed that residues of the ionophore maduramicin (Cygro; American Cyanamid) in poultry litter fed to cattle, after the maduramicin had been incorporated into broiler feed as a coccidiostat, were the cause of the cardiomyopathy. Three groups of 5 heifers were fed for several weeks (1) poultry litter from a field case, containing 4.8 ppm maduramicin; (2) poultry litter to which maduramicin was added to give a concentration of 12 ppm; (3) poultry litter with no maduramicin (control). Clinical, biochemical, necropsy and histopathological findings showed that maduramicin residues are cardiotoxic, even at the lower level of maduramicin fed, which is commonly encountered in poultry litter in Israel.