A case of spontaneous gastric rupture in a 5 years girl.

We describe a case of spontaneous gastric rupture in a child of 5 years old. The patient reached us in a serious condition; the anamnesis was negative for traumatic events or gastrointestinal disorders. An abdominal X-ray and CT scan revealed free air and fluid in the abdominal cavity, leading to the diagnosis of gastro-intestinal perforation. Submitted to urgent surgery, a rupture of the posterior wall of the stomach was found that was treated with gastrectomy "à la demande". The surgery follow-up was regular. Morphological and immunohistochemical study showed some muscular abnormalities of the muscular gastric wall.

Biallelic EPCAM deletions induce tissue-specific DNA repair deficiency and cancer predisposition.

We report a case of Mismatch Repair Deficiency (MMRD) caused by germline homozygous EPCAM deletion leading to tissue-specific loss of MSH2. Through the use of patient-derived cells and organoid technologies, we performed stepwise in vitro differentiation of colonic and brain organoids from reprogrammed EPCAMdel iPSC derived from patient fibroblasts. Differentiation of iPSC to epithelial-colonic organoids exhibited continuous increased EPCAM expression and hypermethylation of the MSH2 promoter. This was associated with loss of MSH2 expression, increased mutational burden, MMRD signatures and MS-indel accumulation, the hallmarks of MMRD. In contrast, maturation into brain organoids and examination of blood and fibroblasts failed to show similar processes, preserving MMR proficiency. The combined use of iPSC, organoid technologies and functional genomics analyses highlights the potential of cutting-edge cellular and molecular analysis techniques to define processes controlling tumorigenesis and uncovers a new paradigm of tissue-specific MMRD, which affects the clinical management of these patients.

Multiple oral and cerebral relapses of a Granular cell tumor (Abrikossoff Tumor) in a young girl affected by congenital dyserythropoietic anemia type II.

CASE REPORT: A 14-year-old girl presented with 1 cm large whitened lesion on the ventral surface of the tongue, appeared from 1 month. Past history showed congenital dyserythropoietic anemia type II. The lesion was excised and microscopic and immunohistochemical analyses were compatible with benign Abrikossoff tumor. Total body MRI was negative. After six months the patient presented a second tongue lesion and four months later another large painful lesion in the soft palate, with the same istological diagnosis. In addition, she had other multiple lesions: two apperead at pharyngeal level (not biopsied) that remain stable over time, and one at the pituitary gland. CONCLUSION: Granular cell tumors, with or without multiple lesions, are rare in children. About 50% of cases involve the head and neck region, with the tongue being the most affected site. Therapy is based on the surgical excision of the lesions; however some tumor forms, although their histological aspect of benignity, often have an important infiltrative power, making the therapeutic approach difficult, as in our case.

Extramedullary hematopoiesis in the facial sinus in a patient homozygous for Hemoglobin Lepore: the first case in literature.

Extramedullary hematopoiesis (EMH) is a proliferation of hematopoietic tissue outside the bone marrow. The most affected areas are paravertebral ones. We report the case of a patient with homozygous Hb Lepore, not regularly transfused since the age of four years until the age of 29 years, when paravertebral heterotopic masses were first observed. After about 10 years she started reporting clinical signs suggestive of sinusitis. Computed tomography (CT) and Magnetic Resonance Imaging (MRI) showed heterotopic masses in the ethmoid and in the frontal sinuses. Involvement of the sinuses of the large facial area represents a rare localization of EMH. Various cases have been reported in patients with thalassemia intermedia, but no case has been reported with HbLepore. The diagnostic gold standard is MRI, which provides highly accurate and clear images. The treatment is based on hydroxyurea and/or an intensive transfusional regime and sometimes on surgery.

[Management of perforations as adverse events of ERCP plus ES. Personal experience]. / Trattamento degli eventi perforativi post-colangiopancreatografia retrograda con sfinterotomia endoscopica. Esperienza personale.

UNLABELLED: INTRODUCTION. ERCP has brought real progress in the study and treatment of pancreatic and biliary diseases, because of its ambivalence as diagnostic and therapeutic procedure. Among its complications, perforations occur in fewer than 1% of patients, but are associated with a mortality rate of 16% -18%. CASE REPORTS: CASE 1- F, 89 years old with obstructive jaundice by choledocholithiasis submitted to ERCP plus ES, during which occurs type II lesion; the partial removing of stones from choledochus during the procedure allow us to opt for a conservative treatment, with resolution on post-ERCP day 12. CASE 2- F, 53 years old with recurring cholangitis and post-cholecystectomy stenosis of choledochus already treated by stenting; for the occurrence of type I lesion during ERCP, the patient undergoes surgery in emergency with healing in postoperative day 23. CASE 3- M, 84 years old with lithiasic cholecystitis, obstructive jaundice, lung emphysema and ischemic heart disease; after percutaneous cholecystostomy in emergency, we attempt to ERCP with evidence of type I lesion. Because of comorbility, we opt for a conservative treatment, not resolving, and then proceed to surgery. Exitus for cardio-respiratory complications. CASE 4- M, 89 years old with obstructive jaundice; ERCP is suspended for respiratory complications and then a PTC is perform; during it we note a type IV lesion, which is treated conservatively with resignation in day 12. CASE 5- F, 68 years old with cholecystitis and choledocholithiasis; during ERCP plus SE a type II lesion occurs with worsening signs of acute abdomen. Because of clinical conditions and the impossibility of carrying out stones from choledochus by endoscopy, we opt for a surgical treatment in emergency. Exitus for respiratory complications. DISCUSSION: Because of the controversy exists on what should be the management of perforations as adverse events of ERCP plus ES (immediate surgery or conservative therapy), we can only hope an eclectic approach based on the anatomical and clinical peculiarity of each case.

Retinal vein occlusion in child with rare mutations in genes for thrombophilia.

INTRODUCTION: Retinal vein occlusions (RVOs) are rare in the younger population. Hematological pro-thrombotic factors are thought to be important in a minority, amplifying an atherosclerotic anatomical predisposition. CASE REPORT: Anotherwise healthy 13-year-old girl presented two episodes of sudden decreased vision in few months.Ophthalmological exams pointed out post-thrombotic intra-retinal hemorrhage. All investigations were normal, thrombophilia screen showed factor XII deficiency and genetic mutations of methylenetetrahydrofolate reductase (MTHFR), angiotesin convertin enzyme (ACE) and angiotensinogen (AGT). Two intravitreal injection of bevacizumab was administered with improving visual acuity; subsequently the patient did not report further episodes. DISCUSSION: In addition to traditional factors with procoagulant activity, factor XII deficiency plays an important role in thrombosis's mechanism. Its deficiency causes a marked prolongation of the activated partial thromboplastin time in the laboratory examination. Moreover also MTHFR, ACE and AGT could have been involved in this case, so it is important to evaluate these parameters in the differential diagnosis of RVOs.

Upregulation of the angiogenic factors PlGF, VEGF and their receptors (Flt-1, Flk-1/KDR) by TSH in cultured thyrocytes and in the thyroid gland of thiouracil-fed rats suggest a TSH-dependent paracrine mechanism for goiter hypervascularization.

Placenta growth factor (PlGF) and vascular endothelial growth factor (VEGF) represent two closely related angiogenic growth factors active as homodimers or heterodimers. Since goiters of the thyroid gland are extremely hypervascular, we investigated the expression of PlGF, VEGF and their receptors, Flt-1 and Flk-1/KDR, in a small panel of human goiters from patients with Graves's disease, in an animal model of thyroid goitrogenesis and in in vitro cultured thyroid cells. Here we report that the mRNA expression of PlGF, VEGF and their receptors is markedly enhanced in biopsies of goiters resected from Graves's patients. In vivo studies demonstrated that in the thyroid gland of thiouracil-fed rats, increased mRNA and protein expression of PIGF, VEGF, Flt-1 and Flk-1/KDR occurred subsequent to the rise in the serum thyroid stimulating hormone (TSH) levels and in parallel with thyroid capillary proliferation. In vitro studies confirmed the existence of such TSH-dependent paracrine communication between thyroid epithelial cells and endothelium since the conditioned medium collected from TSH-stimulated thyrocytes acquired mitogenic activity for human umbilical vein endothelial (HUVE) cells. Altogether, these data suggest that PlGF and VEGF, released by thyrocytes in response to the chronic activation of the TSH receptor pathway, may act through a paracrine mechanism on thyroid endothelium.

Prognostic value of serum biological markers in patients with hepatocellular carcinoma.

PURPOSE: Prognosis of patients with hepatocellular carcinoma (HCC) is assessed by using indexes based on clinical and instrumental parameters. The Cancer of the Liver Italian Program (CLIP) staging system combines the Child-Pugh classification with tumor size, portal invasion, and alpha-fetoprotein and predicts the outcome of HCC patients more precisely than the Okuda staging system. Serum levels of a number of biological variables have been found to be increased in patients with HCC and are associated with different outcomes. Our aims in this study were to test the prognostic role of the serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble interleukin-2 receptor (sIL-2R), interleukin 6 (IL-6), and anti-p53 and to assess whether the addition of any of the above serum markers could further improve the predictive ability of the CLIP score. EXPERIMENTAL DESIGN: Serum levels of sICAM-1, sIL-2R, IL-6, and anti-p53 were assayed in 80 patients with HCC and correlated with their outcomes. Nonparametric procedures were applied to test correlations between serum sICAM-1, sIL-2R, IL-6, anti-p53, and other prognostic factors. For survival analyses, the product-limit method, log-rank test, and Cox proportional hazards model were applied. RESULTS: Only serum levels of sIL-2R correlated with survival, which was longer for patients with lower values (< or =950 units/ml). However, with multivariate analysis sIL-2R did not confirm its predictive role when tested with the CLIP score as a covariate, with a hazard of death of 1.51 (95% confidence interval, 0.76-3.01). CONCLUSIONS: Serum levels of sICAM-1, sIL-2R, IL-6, and anti-p53 are not useful as prognostic factors for HCC in clinical practice. They do not improve the predictive ability of the CLIP score.

Hot-flashes in breast cancer survivors: effectiveness of low-dosage fluoxetine. A pilot study.

Breast carcinoma survivors suffering from hot-flashes experience a negative impact on their quality of life. Antidepressants have recently been proven to be effective in these women, significantly reducing the vasomotor symptoms. With this in mind, a single-arm clinical trial low-dose regimen of Fluoxetine (10 mg/day for 4 weeks) was given to twenty symptomatic breast cancer patients. Among the 12 women evaluated at the end of treatment, a statistically significant reduction of the mean number of daily hot-flashes (-36.3%, p = 0.001) and hot-flashes score (-46.2%, p = 0.0006) had been detected as compared to the baseline data. Although the dosage of Fluoxetine used in these trials was lower than earlier published, it should be noted that these positive results were achieved without any relevant side effects.

Primary leiomyosarcoma of the fallopian tube: a case report.

A primary leiomyosarcoma (LMS) arising from the left fallopian tube in a perimenopausal 48-year-old woman is reported. Primary tubal LMS is an uncommon, exceedingly rare neoplasm, accounting for only a few reported cases so far. To our knowledge, the present case is the 17th tubal LMS reported in the English-language literature. The diagnosis is usually made at the time of laparotomy for a pelvic or adnexal mass or other gynaecological indications. As in ovarian neoplasms, the mainstay of treatment is represented by debulking surgery consisting of total abdominal hysterectomy, bilateral salpingo-oophorectomy, random biopsies, peritoneal washing and excision of all the abdominal tumour masses. Although the approach is radical, the clinical behaviour is very poor. The role of adjuvant radio- or chemotherapy still remains unsolved.

Analysis of chromosomes 3, 7, X and the EGFR gene in uterine cervical cancer progression.

The aim of this study was to investigate the possible role of genetic alterations in the genesis and progression of cervical carcinomas. We analysed the 3, 7, X aneusomy of chromosomes and the status of the epidermal growth factor receptor (EGFR) gene by fluorescence in situ hybridisation (FISH) analysis. Polysomy of chromosomes 3 and X defined the transition from high-grade squamous intraepithelium lesions (HSIL) to cervical carcinoma. Chromosome 7 monosomy and polysomy did not show any statistical significant differences between the groups examined. When we compared the chromosomal aneusomies in all of the specimens using the Kruskal-Wallis test, significant differences (P = 0.0001, P = 0.0001 for chromosomes 3 and X, respectively) were observed. Using a ratio of the EGFR gene signals and chromosome 7 centromeric signals, no samples showed gene amplification. Our results demonstrate the importance of chromosomal 3 and X aneusomies in the development and progression from HSIL to cervical carcinoma, highlighting their usefulness as genetic markers for identifying SILs at high-risk of progression.

Immunological and clinical effects of intramuscular rIFN alpha-2a and low dose subcutaneous rIL-2 in patients with advanced malignant melanoma.

Fifteen patients with tumour recurrence following radical surgical excision of malignant melanoma were treated with a combination of interferon alpha-2a (rIFN alpha-2a) and interleukin-2 (rIL-2). Immunological monitoring (performed prior to therapy and on days 7, 21, and 28, of each course of treatment) showed significant changes of several parameters after rIFN alpha-2a and rIL-2 administration. A significant increase in cells expressing CD16 (cells bearing Fc receptor), CD25 (cells bearing IL-2 receptor), and CD56 (NK cells, activated lymphocytes), as well in levels of soluble IL-2 receptor, beta 2-microglobulin and neopterin was observed. Immunological changes were closely related to the injection of the biological agent and were more relevant during the first than the second cycle of treatment. rIFN alpha-2a and rIL-2 exerted a clear synergistic activity on the same immunological parameters. No major response was seen with the present approach: four subjects showed rapid progression of decrease during the first month of therapy, while of 11 patients who completed two courses of treatment, only five were considered in stable disease. In conclusion, our results suggest that a combination of rIFN alpha-2a and rIL-2, at dosages and schedules, used in this trial, was well-tolerated and immunologically active, but was clinically ineffective in the management of advanced melanoma.

Oestradiol and testosterone blood levels in patients with viral cirrhosis and hepatocellular carcinoma.

BACKGROUND: Patients with alcoholic cirrhosis show hypogonadism and feminization associated with sex hormone imbalance due to enhanced aromatization of testosterone and subsequent reduced testosterone and increased oestradiol blood levels. Because oestrogens modulate hepatocyte proliferation and oestrogen receptors are present in liver cirrhosis and hepatocellular carcinoma, it has been proposed that sex hormone imbalance can play a role in liver carcinogenesis. Trials with the oestrogen receptor antagonist tamoxifen have been performed with conflicting results. OBJECTIVES: To investigate oestradiol and testosterone blood levels in men with viral cirrhosis and hepatocellular carcinoma and also to investigate changes in sex hormone circulating levels induced by tamoxifen treatment. PATIENTS AND METHODS: Oestradiol and testosterone blood levels were evaluated in 32 male patients with postviral cirrhosis and hepatocellular carcinoma at the time of diagnosis and during the follow-up, and in 20 healthy controls. In eight patients, hormone levels were also assayed during treatment with tamoxifen (40 mg/day). No patient had a history of high alcohol intake. RESULTS: Oestradiol values observed at the time of diagnosis were 56.1 +/- 54.5 pmol/l, while testosterone values were 13.6 +/- 8.0 pmol/l. There was no relationship between oestrogen values and age, while higher oestradiol values were observed in patients with advanced cirrhosis (Child B and C); conversely, testosterone levels progressively and significantly decreased from cirrhosis Child A (15.1 +/- 9.7) to C (7.7 +/- 7.1) (P < 0.05). Tamoxifen treatment (40mg/day) for 1 month in eight patients increased oestradiol values (62.2 +/- 77.0 vs. 156.4 +/- 83 pmol/l, P < 0.05), while testosterone levels decreased (15.1 +/- 6.8 vs. 8.5 +/- 10.6 pmol/l). However, these changes were not associated with clinical signs or symptoms of feminization. Oestrogen levels decreased after 6 months of tamoxifen treatment. No significant change in hormone levels was observed in patients not treated with tamoxifen. Unlike patients with alcoholic cirrhosis, in male patients with viral cirrhosis and hepatocellular carcinoma there were no significant alterations in blood oestradiol and testosterone levels, although a certain degree of sex hormone imbalance was observed in those with advanced cirrhosis. Treatment with tamoxifen (40 mg/day) did not induce clinical manifestations of sex hormone imbalance.

Growth and puberty in thalassemia major.

Present transfusional regimen protocols increase the life expectancy of patients with beta-thalassemia major, but cause a progressive iron overload that can be prevented or limited only by appropriate iron chelation. Siderosis is responsible for the clinical complications of the disease. Short stature and hypogonadism are extremely frequent in patients with thalassemia. Many factors are responsible for short stature in patients with thalassemia, the most important of which are dysfunction of the GH-IGF-I axis and desferoxamine (DFX)-induced bone dysplasia. Hypogonadism is the most frequent endocrine complication, mostly due to gonadotrophins deficiency secondary to iron overload. Sex steroid treatment for induction of puberty and/or maintenance of sexual characteristics is necessary. Both short stature and hypogonadism are present in a significant percentage of bone marrow transplanted patients with thalassemia. Factors responsible for short stature are previous iron overload, liver impairment, DFX treatment, and toxicity of chemotherapeutic agents. In some patients absence of pubertal development is due to gonadotropin insufficiency, probably secondary to previous iron overload; other patients exhibit hypergonadotrophic hypogonadism due to the toxic effect of chemotherapeutic agents on the gonads. Both groups need hormonal replacement therapy. These data support the need for vigilant follow-up of patients with thalassemia before and after transplantation, in order to treat endocrine dysfunctions at the appropriate age.

Short-term therapy with recombinant growth hormone in polytransfused thalassaemia major patients with growth deficiency.

Growth failure is commonly described in polytransfused thalassaemia major patients (Th) with or without growth hormone (GH) releasing hormone-GH axis impairment. We have investigated the efficacy of short-term recombinant GH (rhGH) therapy (Saizen [Serono] 0.1 IU/kg/day 6 evenings/week administered s.c. for 12 months) on growth and predicted final height in 28 (19M, 9F) regularly transfused Th with growth deficiency (aged 14.8 +/- 2.0 yr) on long term desferrioxamine s.c. therapy. All Th had no evidence of congestive heart failure, hypothyroidism or impaired glucose tolerance; in all patients the GH peak (evaluated during both insulin and clonidine test) was < or = 20 mIU/l; hypergonadotropic hypogonadism was excluded in Th with delayed puberty. At the start of therapy height age (HA)/bone age (BA) ratio was 0.92 +/- 0.12. Bone age delay was positively correlated to chronological age (CA), serum ferritin levels (mean of the last three years), the age at the start of chelation therapy, growth velocity calculated for CA during the last year; a positive correlation was also found between circulating IGF-I levels and age at the start of chelation therapy. After 1 year on rhGH therapy there was a significant increase of height calculated for CA (not for BA), of growth velocity calculated for both CA and BA and of circulating IGF-I levels; the HA variation/BA variation ratio was 1.85 +/- 1.71, without any significant difference between predicted final height at the start (-1.08 +/- 1.28 SDS) and at the end of rhGH therapy (-0.88 +/- 1.13). The variation of height calculated for CA was positively correlated to both CA and growth velocity during the last year before rhGH therapy (calculated for CA) and negatively to the height at the start (calculated for CA). There were no side effects and haematological parameters did not show significant changes. In conclusion, our data, obtained in a relatively large group of Th, confirm the emerging results of short-term (12 months) rhGH therapy on growth, as shown by the increase of both growth velocity and height calculated for CA. With regard to final height, although the mean variation of HA/variation of BA ratio was 1.85, no significant increase of the predicted final height was found between the start and the end of rhGH therapy. We are evaluating the effect of long-term rhGH therapy on growth in these patients.

Recombinant growth hormone treatment in short patients with thalassemia major: results after 24 and 36 months.

Treatment with recombinant growth hormone (rhGH), 0.6 IU/kg/week s.c., previously successfully conducted for one year, was continued in 15 (Group A) and 8 (Group B) short thalassemia major patients with reduced GH reserve, for two and three years, respectively. In Group A, height for chronological age (Ht SDSCA) increased significantly (p = 0.021) from the start of treatment, but the positive effect was only apparent because of the concomitant slight worsening of height for bone age (Ht SDSBA). Median deltaHt SDSCA/deltaHt SDSBA was <1.0 with respect to both the start (0.87) and the end of the first year of rhGH therapy (0.89). IGF-I levels increased significantly (p = 0.043) compared with values both at the start and at the end of the first year of rhGH therapy. In Group B neither Ht SDSCA nor Ht SDSBA differed statistically from starting values, the former having a positive trend and the latter a negative one. Median deltaHt SDSCA/deltaHt SDSBA was 0.92 with respect to the start, and 0.94 with respect to the end of the second year. IGF-I levels increased significantly (p = 0.043) with respect to starting values. Our data show that the encouraging results described from the first year of rhGH treatment did not persist during the second and third years, and we conclude that this is because increase in bone age with continued treatment is equal to, or slightly greater than the height age increase. We propose that patients with thalassemia major with short stature should receive rhGH treatment for only one year, and that more prolonged treatment should be reserved for selected adolescents who have psychological problems due to shortness; for these patients growth acceleration could represent the main goal, even if this leads to a substantially unchanged or slightly decreased final height.

Short stature and body proportion in thalassaemia.

Short stature and short trunk have been reported in thalassaemic patients. We report a study on stature and body proportions in 476 patients (2-36 years old) with beta-thalassaemia major, followed in 12 Italian centres. Auxological data (standing height, sitting height, subischial leg length, target height), haematological data (age at first transfusion, age at start of desferrioxamine [DFX] chelation, mean dose of DFX, ferritin values) and information regarding the presence of endocrine disorders and of bone lesions, were collected and analysed according to the age of the patients, in order to investigate the natural history of the disproportion and the role of siderosis, DFX toxicity and endocrine disorders. Our data indicate that about 18% of thalassaemic patients exhibit short stature; disproportion between the upper and lower body segments is present in 14%; however, a short trunk despite normal stature is present in another 40% of patients. This is due to a spinal growth impairment which starts in infancy and progressively aggravates. We think that a short trunk is peculiar to the disease itself; however, other factors such as hypogonadism, siderosis, or DFX-induced bone dysplasia are probably involved in aggravating the body disproportion in these patients.

Ondansetron-induced headache. Our experience in gynecological cancer.

Chemotherapy-induced emesis is one of the major problems in the treatment of oncologic patients. Recently, a novel class of compounds, the selective 5HT3 receptor antagonists, has been introduced, achieving a dramatic improvement in the control of emesis. The absence of extrapyramidal side effects adds to their safety and good tolerability. The Authors herein analyse their experience on 269 cycles of chemotherapy in 47 patients treated for gynaecological and breast malignancies, with particular regard to adverse events such as headache. Their most frequent side-effects are headache and constipation, that are usually mild and self-limiting. Nevertheless, in some cases, severe, rebel headache has been reported, leading in our experience in 6.4% of cases to discontinuation of the antiemetic regimen. A previous history of recurrent or severe headache or migraine is not correlated with the occurrence of ondansetron-induced headache, as severe headache occurred after ondansetron only in 28.4% of the patients with positive anamnesis, and 70% of the patients that experienced had never suffered from severe headache before. In those patients complaining of severe headache, the Authors suggest an antiemetic association, with a loading dose of ondansetron i.v., followed by metoclopramide i.m. orally for the following days.

Assessment of risk factors and human papillomavirus (HPV) related pathogenetic mechanisms of CIN in HIV-positive and HIV-negative women. Study design and baseline data of the HPV-PathogenISS study.

OBJECTIVES: In women with HIV-associated immunosuppression, HPV infections have an increased risk of progression to high-grade cervical intraepithelial neoplasia (CIN). With the HAART-induced prolonged survival and more protracted clinical course of AIDS, progression of CIN to cervical cancer (CC) has become a clinically relevant issue, and the mechanisms responsible for HIV-HPV interactions need further elucidation. The study design and analysis of the baseline data of our new project are presented. MATERIAL AND METHODS: This project is a combination of a prospective cohort study of HIV- and HIV+ women, and a retrospective analysis of CIN lesions and cervical cancer. Up to the present, 244 women have been enrolled (17 HIV+) and subjected to epidemiological interview, colposcopic examination, sampling for HPV testing and typing (PCR, InnoLiPA), and HPV serology. The retrospective series of biopsies were analysed for 13 biomarkers (monitoring key molecular events) using immunohistochemistry and tested for HPV by PCR and TaqMan. RESULTS: HIV- and HIV+ women differ in their exposure status to many of the key epidemiological risk factors of cervical cancer, the most significant ones being number of sexual partners (p = 0.0001), age at onset of sexual activity (p = 0.002), and contraception (yes-no) (p = 0.009). The differences in the baseline clinical observations are less dramatic; HIV-positive women had more frequent HSIL PAP tests (p = 0.040), CIN2 or higher in cervical biopsy (p = 0.049), and external genital warts (p = 0.019). The factors predicting intermediate endpoint markers of cervical cancer, i.e., HSIL PAP smear, ATZ2 in colposcopy, and high-grade CIN in biopsy were analysed in univariate and multivariate regression models. All factors significant in univariate analysis were entered in the multivariate model; HIV-status and Pap smear history maintained their independent predictive power of the HSIL Pap test. The most powerful predictor of ATZ2 colposcopy was HSIL in Pap test. Only the HSIL Pap test and ATZ2 colposcopy remained significant independent predictors of high-grade CIN (p = 0.0001 and p = 0.008, respectively) in the multivariate model. CONCLUSIONS: The three intermediate endpoint markers are closely interrelated, but predicted in part by different covariantes in the causal pathway to cervical cancer. To elucidate whether the increased risk of HIV-positive women to high-grade CIN is due a) to their different exposure status to the risk factors, b) to the direct effects of HIV, or c) to molecular interactions between HIV and HPV, we need to complete these analyses separately in HIV+ and HIV- women.