On the impact of surveillance test strategies: a cost-benefit modelling analysis based upon real-world data from SARS-CoV-2.

OBJECTIVES: Active regular surveillance testing of asymptomatic and symptomatic individuals can reduce infection and onward transmission rates, as demonstrated for SARS-CoV-2. STUDY DESIGN: Cost-benefit analysis based on real-world data. METHODS: Two different surveillance-testing strategies using nucleic acid amplification tests (NAATs) performed in 14,177 hospital employees were compared for their costs and their effectiveness in preventing secondary infections. RESULTS: Compared to not testing, NAAT-based testing twice a week accompanied by contact tracing or testing five times a week without tracing of contacts were more effective in preventing infections through early identification of infected individuals. While expansion of the test frequency from two to five times per week increased the initial costs, importantly, a 49.6 % higher inhibitory effect on infection growth with a 11.1-fold reduction of potentially averted infections and resulting workforce loss was observed, demonstrating a substantial cost-benefit of the 5-tests-per-week strategy. CONCLUSIONS: Adaptation of the test frequency of SARS-CoV-2 and possibly of other pathogens with epidemic potential according to the prevailing incidences and reproduction rates in high-prevalence situations may not only be beneficial in averting potential infections in hospital employees and, subsequently, on a population level but may also represent the most cost-effective method.

Detection of a knockdown mutation in the voltage-sensitive sodium channel associated with permethrin tolerance in Sarcoptes scabiei var. hominis mites.

BACKGROUND: Increasing evidence has sparked a debate on the loss of sensitivity of scabies mites to conventional permethrin therapy. Mutations in the voltage-sensitive sodium channels (VSSC) were associated with knockdown resistance (kdr) in many arthropods, but have never been identified in Sarcoptes scabiei variatio (var.) hominis mites. OBJECTIVES: To identify factors contributing to therapy failure. METHODS: Sixty-seven mites were collected from 64 scabies-infested patients in Vienna, Austria, of whom 85.9% were refractory to prior permethrin-based treatments, and genotyped for the presence of nucleotide polymorphisms in Domain II of the VSSC, known to be associated with kdr. Information regarding previous antiscabietic therapies, decontamination procedures and possible re-infestations by contacts as well as the response to re-imposed therapies were obtained. RESULTS: Sequence alignment comparisons revealed previously unidentified mutations in the coding region of Domain II of the VSSC. A novel A1663T transversion was detected in 97.0% of the mites, resulting in a non-synonymous substitution from methionine to leucine, M918L, a mutation known to confer kdr in other arthropods. In addition, a synonymous G1659A transition was identified in one mite, which otherwise showed a nucleotide sequence identical to the wild-type reference. No major inconsistencies were observed within the previous therapeutic and decontamination procedures, which could have accounted for the observed non-responsiveness to permethrin-based therapies. Subsequent cure of infestation was achieved in 65.6% of the participants, predominantly by combination therapies with topical permethrin and systemic ivermectin. However, in 14.6% of the cured cases, permethrin monotherapy sufficed for eradication of scabies, albeit in some cases prolonged exposure was necessary. CONCLUSIONS: The kdr-associated M918L mutation in the VSSC gene has now emerged in S. scabiei var. hominis mites. Hence, loss of sensitivity to permethrin due to kdr-type resistance may be more prevalent than anticipated and may be decisive for the therapy responsiveness of scabies-infested patients.

Effect of intravenous immunoglobulin administration on erythrocyte and leucocyte parameters.

BACKGROUND: Intravenous immunoglobulins (IVIG) are an attractive therapeutic tool for therapy of toxic epidermal necrolysis and severe forms of certain autoimmune diseases, including dermatomyositis, autoimmune blistering diseases, systemic vasculitis and lupus erythematodes. OBJECTIVES: Prompted by a case of IVIG-associated haemolytic anaemia, the effects of IVIG administrations on haematological parameters in patients with dermatological conditions were investigated. METHODS: Erythrocyte and leucocyte parameters were retrospectively analysed in 16 patients who had received IVIG at doses from 1 to 3 g/kg bodyweight (n = 35 cycles). The influence of IVIG on leucocyte survival was determined in vitro. RESULTS: Decreased absolute erythrocyte numbers, haemoglobin and haematocrit levels and a case of haemolytic anaemia were linked to transfusion of high-, but not low-dose IVIG. In contrast, leucopenia post-IVIG occurred in the vast majority of the recipients, unrelated to the administered IVIG amounts. In vitro investigations revealed a dose-dependent impairment of cell survival by IVIG in the neutrophil and monocyte, but not in the lymphocyte subpopulations. In several IVIG preparations, substantial amounts of blood group anti-A/anti-B antibodies were detected which could have accounted for the observed changes in the haematological parameters in our study cohort. CONCLUSIONS: IVIG products should be administered strictly according to indications. Commercially available IVIG products can contain blood group-specific antibodies that may induce haemolysis in some recipients. Monitoring of blood counts during applied IVIG therapy, especially when high doses are administered, is recommended.

Human papillomavirus vaccination induces neutralising antibodies in oral mucosal fluids.

BACKGROUND: Mucosal human papillomaviruses (HPV) are a major cause of cancers and papillomas of the anogenital and oropharyngeal tract. HPV-vaccination elicits neutralising antibodies in sera and cervicovaginal secretions and protects uninfected individuals from persistent anogenital infection and associated diseases caused by the vaccine-targeted HPV types. Whether immunisation can prevent oropharyngeal infection and diseases and whether neutralising antibodies represent the correlate of protection, is still unclear. METHODS: We determined IgG and neutralising antibodies against low-risk HPV6 and high-risk HPV16/18 in sera and oral fluids from healthy females (n=20) before and after quadrivalent HPV-vaccination and compared the results with non-vaccinated controls. RESULTS: HPV-vaccination induced type-specific antibodies in sera and oral fluids of the vaccinees. Importantly, the antibodies in oral fluids were capable of neutralising HPV pseudovirions in vitro, indicating protection from infection. The increased neutralising antibody levels against HPV16/18 in sera and oral fluids post-vaccination correlated significantly within an individual. CONCLUSIONS: We provide experimental proof that HPV-vaccination elicits neutralising antibodies to the vaccine-targeted types in oral fluids. Hence, immunisation may confer direct protection against type-specific HPV infection and associated diseases of the oropharyngeal tract. Measurement of antibodies in oral fluids represents a suitable tool to assess vaccine-induced protection within the mucosal milieu of the orophayrynx.

[HPV infections of the oral and genital mucosa. Possibilities for primary prevention]. / HPV-Infektionen der Mund- und Genitalschleimhaut. Möglichkeiten der primären Prävention.

It is well accepted today that almost all cases of carcinoma of the cervix are caused by persistent infections with high-risk human papilloma viruses (HPV), especially through types HPV16 and HPV18 (ca. 70%). These same types are also responsible for some carcinomas of the vulva, anus, penis and oropharynx. This knowledge indicates that it should be possible to prevent these carcinomas if a majority of the causstive HPV infections can be prevented.

Rapid progression of an anal Buschke-Lowenstein tumour into a metastasising squamous cell carcinoma in an HIV-infected patient.

BACKGROUND: Buschke-Löwenstein tumour (BLT) of the anogenitalia is a locally invasive, destructively growing verrucous carcinoma that does not metastasise. Histologically BLT resembles benign condylomata acuminata. Nevertheless, the tumour grows relentlessly and may rarely progress into squamous cell cancer (SCC). RESULTS: A human immunodeficiency virus (HIV)-infected immunosuppressed patient developed (peri)anal warts accompanied by recurrent abscesses and fistulae. Histology revealed condylomata acuminata, and low-risk genital human papillomavirus (HPV) type 11b was detected. Six months later, the tumour had progressed into an ulcerated SCC that destroyed the rectum and perineum, with metastases to the inguinal lymph nodes. Whereas highly active antiretroviral therapy (HAART) effectively suppressed HIV replication, radiochemotherapy plus anti-EGFR antibody did not halt tumour progression, and the patient died from tumour-cachexia. DISCUSSION: As far as is known, this is the first report demonstrating rapid progression of a BLT into a metastasising SCC in an HIV-infected patient.

Metabolic diseases and associated complications: sex and gender matter!

BACKGROUND: Clinicians and health professionals are increasingly challenged to understand and consider the different health needs of women and men. The increase of gender awareness and the expanding science of gender medicine will affect more and more clinical practice. This review addresses gender-specific aspects in metabolic disorders and related complications, which represent an increasing burden of this century and a great challenge to public health. DESIGN: There is increasing evidence of gender-related differences in risk factors, clinical manifestation and sequelae of obesity and diabetes and increasing knowledge that prevention, detection and therapy of illness affect men and women differently. RESULTS: Some gender-specific aspects, especially regarding cardiovascular disease, have been studied in more detail, but for many complications sex-related analyses of the results of both clinical trials and basic science are still missing or disregarded. Impaired glucose and lipid metabolism as well as dysregulation of energy balance and body fat distribution have a great impact on overall health via neuroendocrine changes and inflammatory pathways and deteriorate the course of many diseases with particular harm for women. Metabolic diseases dramatically affect life of men and women from infancy up to old age and are a major challenge for women during pregnancy. Great impact is attached to the intrauterine period and the lifelong implications of fetal programming. CONCLUSIONS: Initiation of prospective studies on the impact of gender as primary outcome and investigation of gender-related pathophysiological mechanisms of chronic diseases will help to improve patient care and to implement evidence-based gender-specific prevention programs and clinical recommendations in future.

SDRIFE (baboon syndrome) induced by penicillin.

We report a patient who developed a drug rash after systemic administration of amoxicillin. After oral re-exposure to the alternative beta-lactam antibiotic phenoxymethylpenicillin, the patient developed a sharply demarcated V-shaped erythema of the inguinal region, the thighs, and the gluteal area, resembling the buttocks of baboons. Historically, the condition coined 'baboon syndrome' was described as a special entity of a mild systemic cutaneous erythema after oral exposure to type IV allergens, such as nickel, mercury or drugs. Recently, it has been proposed to replace this term by the acronym SDRIFE (symmetrical drug-related intertriginous and flexural exanthema) for those reactions occurring after exposure to systemic drugs.

Insulin resistance has no impact on ghrelin suppression in pregnancy.

Ghrelin is reduced in various states of insulin resistance. The aim of this study was to examine the relationship between ghrelin and glucose metabolism during pregnancy - a natural insulin-resistant state - in women with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or gestational diabetes mellitus (GDM) and potential changes 3 months after delivery. A total of 54 women, 37 pregnant and with various degrees of insulin resistance and 24 postpartum (PP, seven of them also studied during pregnancy) were studied. Ghrelin plasma concentrations at fasting and 60' following glucose loading (75 g-2 h-oral glucose tolerance test), area under the curve of plasma glucose (G-AUC(OGTT)) and insulin sensitivity [homeostatic model assessment (HOMA) and oral glucose sensitivity index (OGIS) indices, respectively] were determined. Both baseline and 60' ghrelin concentrations were to a comparable degree ( approximately by 65%) suppressed in NGT, IGT and GDM as compared to the PP group (the latter being indistinguishable from NGT regarding glucose tolerance and insulin sensitivity). In all women studied both during and after pregnancy, ghrelin levels rose from pregnancy to PP (mean increase 313.8%; P < 0.03). There was no correlation between baseline ghrelin and insulin sensitivity as estimated from both baseline (HOMA) and dynamic (OGTT:OGIS) glucose and insulin data. Ghrelin is substantially decreased during pregnancy, but glucose-induced ghrelin suppression is preserved at a lower level. There is apparently no relation to the degree of insulin resistance.

Human papillomavirus type 26 infection causing multiple invasive squamous cell carcinomas of the fingernails in an AIDS patient under highly active antiretroviral therapy.

Squamous cell carcinoma (SCC) of the nail unit is a rare disorder. An association with high-risk genital human papillomavirus (HPV) infection has been reported. We report a 28-year-old human immunodeficiency virus (HIV)-infected bisexual man who had multiple invasive SCC of the fingers, infected with the rare type HPV 26. Classification of HPV 26 as high- or intermediate-risk type has been uncertain, due to its rare presence in cervical cancer. Despite successful treatment with highly active antiretroviral therapy (HAART), the patient developed extensive hyperkeratotic nailbed proliferations of all fingers. Tumours were refractory to treatment and invaded into adjacent tissues. X-rays of the hands demonstrated bone invasion, necessitating amputation of distal phalanges of several fingers. Histologically, highly differentiated preinvasive and invasive verrucous SCCs were identified. Molecular DNA typing identified HPV 26 in the SCCs and in some premalignant lesions. By in situ hybridization HPV 26 DNA was detected in numerous tumour cells, indicating productive infection with high-level amplification of the viral genome. In the remaining proliferations, high-risk HPV type 58, cutaneous HPVs and a putative new HPV type were identified. HPV 26 infection appears to be causally involved in the development of SCC of the nail unit in this immunosuppressed patient. Timely evaluation of chronic verrucous nailbed tumours is recommended, especially in immunocompromised patients. Identification of HPV 26, besides known high-risk HPV types, may identify patients at risk for developing SCC of the nailbed and possibly at other locations.

Differential expression of interleukin-15, a pro-inflammatory cytokine and T-cell growth factor, and its receptor in human prostate.

BACKGROUND: Pro-inflammatory interleukin (IL)-15 plays a major role in host defense and chronic inflammation by stimulating T-lymphocyte recruitment and growth. Expression of IL-15 and IL-15 receptor (IL-15R) in human prostate was examined. METHODS: Normal and benign hyperplastic (BPH) prostate specimens (n = 23) were analyzed for IL-15 and IL-15Ralpha-chain expression by immunohistochemistry and Real-Time-PCR/RT-PCR. Regulation of prostatic stromal cell (PSC) IL-15 mRNA and effect of IL-15 on prostatic cell growth were analysed in vitro. RESULTS: In normal prostate, anti-IL-15 and anti-IL-15Ralpha-chain reactivity were restricted to smooth muscle and stromal cells. However, in BPH, in addition epithelial cells frequently exhibited discrete anti-IL-15R and often intense, membranous anti-IL-15 reactivity. IL-15/IL-15R mRNA were detected in all prostatic cells types. In BPH tissues, IL-15 mRNA content was variable (15-fold). IL-15 mRNA synthesis of PSC was significantly up-regulated by IFN-gamma. Furthermore IL-15 strongly stimulated the growth of BPH-T-lymphocytes and weakly that of carcinoma cell lines, but not of stromal cells. CONCLUSIONS: Overexpression of IL-15 and IL-15Ralpha-chain in BPH and massive proliferation of BPH-T-lymphocytes induced by IL-15 suggest a role for IL-15 in prostatic inflammation. Since IFN-gamma, a T-lymphocyte product, stimulates prostatic IL-15 production; chronic inflammation might be triggered by this paracrine loop.

Human accessory cells activate fresh, normal, tumor-distant T lymphocytes but not tumor-infiltrating T lymphocytes to lyse autologous tumor cells in a primary cytotoxic T lymphocyte assay in renal cell carcinoma.

OBJECTIVES: Search for an ideal responder T-lymphocyte source for adoptive T-lymphocyte therapy in renal cell carcinoma (RCC). METHODS: Cytotoxic T-lymphocyte (CTL) activity of (a) normal, tumor-distant, renal T lymphocytes, (b) tumor-infiltrating T lymphocytes and (c) peripheral blood T lymphocytes against autologous tumor epithelial cells (EC) of 10 patients with organ-confined, primary RCC was analyzed in a primary CTL assay. Freshly enriched T lymphocytes were cultured with or without autologous, mitomycin-C-treated normal or tumor EC in the presence or absence of antigen-presenting cells (APC) for 7 days. RESULTS: Both tissue T-lymphocyte populations displayed a similar CD4:CD8 ratio (1:1). Elevated CD62L coexpression of CD4+ T lymphocytes in normal, tumor-distant, renal tissue resulted in a significantly higher transient T-cell activation than that seen in renal tumor tissue (46 vs. 27%; p = 0.002). All trials to induce significant lysis of autologous, renal tumor EC in tumor-infiltrating and peripheral blood T lymphocytes failed. Only when normal, tumor-distant, renal T lymphocytes were stimulated by autologous APC and tumor EC was significant autologous tumor EC lysis obtained (mean 14%; p<0.05). Costimulation by anti-CD3 (mean 21%; p<0.05) or interleukin-2 (mean 31%; p<0.05) further increased tumor EC lysis significantly. CONCLUSIONS: Increased turnover of T lymphocytes in normal, tumor-distant, renal tissue was associated with a higher yield of pre-CTL which can be transformed into a functionally active effector T-cell pool by stimulation via antigen plus APC. Thus, tumor-distant renal tissue has to be included in the tissue-sampling procedure for adoptive immunotherapy.

Expression of cytokeratin-18-related tissue polypeptide-specific (TPS) antigen in Wilms tumor.

BACKGROUND: So far, there is no approved tumour marker for diagnosis or follow-up in Wilms tumour (WT). Tissue polypeptide-specific antigen (TPS), a cytokeratin 18 proteolytic fragment, has been suggested to be of value in the clinical management of WT patients. Cytokeratin 18 fragments are an early indicator of apoptosis and cytokeratin 18 might influence tumour cell behaviour. We investigated TPS expression in specimens of WT and other paediatric renal malignancies PROCEDURE: Immunoreactivity of WT sections (n = 9), clear cell sarcomas (CCSK, n = 3), and a renal cell carcinoma (RCC), and two pediatric kidney tumour cell lines (WT: SK-NEP-1 and rhabdoid tumour of the kidney: G-401) were investigated using the monoclonal antibody M3. Additionally, immunoblotting and RT-PCR analysis were performed. Cell culture supernatants were evaluated for TPS release. Serum TPS was measured in five patients at diagnosis, during chemotherapy and after surgical resection. RESULTS: Moderate to strong immunoreactivity for TPS was found in tubular and blastemal components of nearly all (8/9) WT specimens. This was confirmed by Western-blotting. Cystic and epithelial-like portions of CCSKs and RCC showed distinct reactivity (3/3). The supernatant of G-401 but not of SK-NEP-1 showed a time- and cell number-dependent increase of TPS release. Interestingly, TPS synthesis was demonstrated in SK-NEP-1 cells. Median preoperative serum TPS was elevated (293 U/l) compared to healthy children and lowest after surgical resection (49.5 U/l). CONCLUSIONS: This is the first study demonstrating the synthesis and release of TPS by WTs and other paediatric renal malignancies. Considering the elevated levels of TPS in serum of these patients, a further investigation of this marker by larger clinical trials seems to be justified.

Local intratumoral tumor necrosis factor-alpha and systemic IFN-alpha 2b in patients with locally advanced prostate cancer.

To examine tolerability and activity of local, intratumoral tumor necrosis factor-alpha (TNF-alpha) and systemic interferon-alpha2b (IFN-alpha2b) in locally advanced, hormone-resistant prostate cancer (LA-HRPC), 10 patients with LA-HRPC (T4N x M0, n = 3, T4N x M1, n = 5; T4N1M1, n = 2) were treated with recombinant TNF-alpha injected locally into prostate tumor tissue at 4-week intervals (maximum of four cycles) combined with intermittent subcutaneous (s.c.) administration of 5 x 10(6) IU IFN-alpha2b. Twenty-nine TNF-alpha cycles were administered. Despite significant TNF-alpha leakage into the systemic circulation 2 h after intraprostatic application (from a mean of 9 to a mean of 416 pg/ml; p = 0.0034), TNF-alpha (and IFN-alpha2b) was well tolerated (WHO grade 1-2 toxicity), possibly because of its rapid neutralization by increasing soluble 55-kDa and 75-kDa TNF receptor levels in the serum (mean increase 268% and 91%, respectively) at the same time. TNF-alpha induced prostate tumor cell necrosis in all patients, leading to a significant reduction of prostate volume in 9 of 10 cases (mean 38%; p = 0.0025). The significant short-term increase of prostate-specific antigen (PSA) (mean 65%; p < 0.001), tissue polypeptide-specific antigen (TPS) (mean 85%; p = 0.001), and possibly interleukin-8 (IL-8) (mean 2687%; p < 0.009) serum levels within 4 h after TNF-alpha confirmed the cytotoxic effect in vivo. In the long term, serum PSA levels dropped by 18%-87%, reaching the nadir value 7 weeks after baseline. Objective responses of metastases were not seen. Intraprostatic administration of TNF-alpha is feasible at a tolerable toxicity in patients with LA-HRPC and, thus, may be a new treatment option for these patients.

Vascular endothelial growth factor receptor 2 (VEGFR2) expression in squamous cell carcinomas of the head and neck.

OBJECTIVES: Vascular endothelial growth factor receptor 2 (VEGFR2; Flk-1 [fetal liver kinase]/KDR [kinase insert domain containing receptor]) has been identified as a high affinity receptor for vascular endothelial growth factor (VEGF) on vascular endothelium. Head and neck squamous cell carcinomas (HNSCC) have already been shown to produce substantial amounts of VEGF. VEGFR2 is supposed to play a major role in tumor-neoangiogenesis. METHODS: We investigated 24 tumor specimens and 4 HNSCC cultured tumor cell lines for the incidence and distribution of VEGFR2 by immunohistochemistry using monoclonal antibodies (mAbs) and RT-PCR. RESULTS: Analysis of frozen sections by immunohistochemistry showed that in 90% of tumor specimens VEGFR2-positive cells were found which were associated with vascular endothelium. VEGFR2 was also expressed on tumor cells and vessels, which was confirmed by double immunolabeling of tumor cells with an a-cytokeratin mAb. Furthermore, 2 (JPPA, SCC9) of 4 HNSCC cultured tumor cell lines revealed positive VEGFR2 immunoreactivity. Synthesis of VEGFR2 mRNA on all 4 HNSCC cultured tumor cell lines (JPPA, SCC9, SCC25, and LFFR) and in 6 tumor specimens was confirmed by RT-PCR. In conclusion, our results showed that VEGFR2 is expressed in HNSCCs on tumor cells. VEGFR2 expression is associated with the beginning of vasculogenesis represented by accumulation of VEGFR2-positive cells budding into new vessels ("hot spots"). The focal expression pattern of VEGFR2 on tumor cells suggests an autocrine loop for VEGF in tumor cell growth.

Expression of the VEGF-receptor Flt-1 in benign, premalignant and malignant prostate tissues.

PURPOSE: Vascular endothelial growth factor (VEGF) is one of the most potent regulators of angiogenesis and has been shown to act upon two tyrosine kinase family receptors: c-fms-like tyrosine kinase (Flt-1) and fetal liver kinase. Preliminary reports have emphasized that expression of VEGF receptors is endothelial cell-specific. In this study we verified the localization and distribution of Flt-1 protein and mRNA expression in prostatic adenocarcinoma (CaP) as well as prostate intraepithelial neoplasia (PIN) and benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: 30 selected surgical specimens exhibiting areas with CaP, PIN and BPH histology were evaluated for Flt-1 protein expression by immunohistochemistry. Results were compared with tumor differentiation (Gleason-Score), serum-PSA and clinical followup. Flt-1 synthesis by prostatic carcinoma cell lines, freshly isolated BPH epithelial cells (BPH-EC) and stromal cells was investigated using RT-PCR and intron spanning primer. RESULTS: VEGF receptor Flt-1 specific anti-sera revealed significant staining of prostatic endothelial cells, but the reactivity was not restricted to endothelial cells. BPH-epithelial cells of all specimens reacted significantly with anti-Flt-1. In contrast, tumor cells failed to react with anti-Flt-1 in 56% of the specimens. BPH-EC revealed a uniform anti-Flt-1 reactivity, which was less pronounced and weaker in PIN. Loss of anti-Flt-1 reactivity of prostatic tumor cells did not correlate with preoperative PSA serum levels but increased with tumor dedifferentiation. Interestingly, tumor cells of all CaP specimens with a Gleason score of >8 exhibit no anti-Flt-1 immunoreactivity. Accordingly while PC3, DU145 and LNCaP cells were negative when tested using RT-PCR all BPH tissue derived BPH-EC revealed Flt-1 coding mRNA expression. CONCLUSIONS: Widespread distribution of VEGF receptor Flt-1 in BPH, PIN and prostate cancer specimens suggests that VEGF function in prostate is not restricted to endothelial cells and angiogenesis. However, since the receptor is lost in CaP cells and with tumor dedifferentiation, these yet unknown effects of VEGF on epithelial cells are obviously suppressed with malignant transformation.

The relationship of pretreatment serum hemoglobin level to the survival of epithelial ovarian carcinoma patients: a prospective review.

BACKGROUND: Tumor anemia is a common symptom in cancer patients. This study assessed the prognostic relationship of pretreatment serum hemoglobin levels to survival in a retrospective sample of 206 patients with epithelial ovarian carcinoma. METHODS: Survival analysis was evaluated by univariate (Kaplan-Meier product limit method and log rank test) and multivariate (Cox proportional hazards model) analysis. Mean values were compared by the Kruskal-Wallis test. Serum hemoglobin levels were determined in each patient 24-48 hours before surgery. Anemia was defined as a serum hemoglobin value below 12 g/dL. RESULTS: Tumor anemia was present in 32% of the patients before primary surgery. Hemoglobin levels were significantly lower in patients with residual tumor than in those with no detectable residual tumor after initial surgery (P = 0.008). Although statistically not significant, we found a trend toward lower hemoglobin levels with advanced stage of disease. For 5 years, overall survival probability was 38.5% and 52.3% for patients with pretreatment hemoglobin levels P = 0.008). In multivariate analysis, the relative risk of death was significantly associated with decreasing serum hemoglobin levels. No interaction was found between the grade of anemia and chemotherapy or radiation therapy with respect to its influence on overall survival. CONCLUSIONS: After adjustment for established prognostic factors, tumor anemia was found to have an independent relationship to the overall survival of patients with ovarian carcinoma. Because no significant interaction could be found between the grade of anemia and chemotherapy, marked tumor anemia was considered an indicator of the presence of biologically aggressive tumor cell clones.