Multicancer screening test based on the detection of circulating non haematological proliferating atypical cells.

BACKGROUND: the problem in early diagnosis of sporadic cancer is understanding the individual's risk to develop disease. In response to this need, global scientific research is focusing on developing predictive models based on non-invasive screening tests. A tentative solution to the problem may be a cancer screening blood-based test able to discover those cell requirements triggering subclinical and clinical onset latency, at the stage when the cell disorder, i.e. atypical epithelial hyperplasia, is still in a subclinical stage of proliferative dysregulation. METHODS: a well-established procedure to identify proliferating circulating tumor cells was deployed to measure the cell proliferation of circulating non-haematological cells which may suggest tumor pathology. Moreover, the data collected were processed by a supervised machine learning model to make the prediction. RESULTS: the developed test combining circulating non-haematological cell proliferation data and artificial intelligence shows 98.8% of accuracy, 100% sensitivity, and 95% specificity. CONCLUSION: this proof of concept study demonstrates that integration of innovative non invasive methods and predictive-models can be decisive in assessing the health status of an individual, and achieve cutting-edge results in cancer prevention and management.

Leiomyoma or sarcoma? MRI performance in the differential diagnosis of sonographically suspicious uterine masses.

PURPOSE: To assess the diagnostic performance of MRI in distinguishing between leiomyomas and malignant/potentially malignant mesenchymal neoplasms in patients with rapidly enlarging/sonographically suspicious uterine masses. METHODS: IRB-approved retrospective study including 88 patients (51 ± 11 years) who underwent MRI for rapidly enlarging/sonographically suspicious uterine mass at our Institution between January 2016 and December 2021, followed by surgery or >12 months follow-up. Qualitative image analysis was independently performed by 2 radiologists and included lesion's margins (sharp/irregular), architecture (homogeneous/inhomogeneous), presence of endometrial infiltration (yes/no), necrotic areas (yes/no), hemorrhagic areas (yes/no), predominant signal intensity on T1-WI, T2-WI, CE T1-WI, DWI, and ADC map. The same radiologists performed quantitative image analysis in consensus, which included lesion's maximum diameter, lesion/myometrium signal intensity ratio on T2-WI and CE T1-weighted images, lesion/endometrium signal intensity ratio on DWI and ADC map and necrosis percentage. Lesions were classified as benign or malignant. Imaging findings were compared with pathology and/or follow-up. RESULTS: After surgery (52/88 patients) or follow-up (36/88 patients, 33 ± 20 months), 83/88 (94.3%) lesions were classified as benign and 5/88 (5.7%) as malignant/potentially malignant. Presence of necrotic areas, high necrosis percentage, hyperintensity on DWI and high lesion/endometrium DWI signal intensity ratio were significantly associated with malignant/potentially malignant lesions (p = 0.027, 0.002, 0.008 and 0.015, respectively). The two readers identified malignant/potentially malignant lesions with 95.5% accuracy, 80.0% sensitivity, 96.4% specificity, 57.1 % PPV, 93.3% NPV. CONCLUSION: MRI has high accuracy in identifying malignant/potentially malignant myometrial masses. In everyday practice, however, MRI positive predictive value is relatively low given the low pre-test malignancy probability.

Relevance of the College of American Pathologists guideline for validating whole slide imaging for diagnostic purposes to cytopathology.

Whole slide imaging (WSI) allows pathologists to view virtual versions of slides on computer monitors. With increasing adoption of digital pathology, laboratories have begun to validate their WSI systems for diagnostic purposes according to reference guidelines. Among these the College of American Pathologists (CAP) guideline includes three strong recommendations (SRs) and nine good practice statements (GPSs). To date, the application of WSI to cytopathology has been beyond the scope of the CAP guideline due to limited evidence. Herein we systematically reviewed the published literature on WSI validation studies in cytology. A systematic search was carried out in PubMed-MEDLINE and Embase databases up to November 2021 to identify all publications regarding validation of WSI in cytology. Each article was reviewed to determine if SRs and/or GPSs recommended by the CAP guideline were adequately satisfied. Of 3963 retrieved articles, 25 were included. Only 4/25 studies (16%) satisfied all three SRs, with only one publication (1/25, 4%) fulfilling all three SRs and nine GPSs. Lack of a suitable validation dataset was the main missing SR (16/25, 64%) and less than a third of the studies reported intra-observer variability data (7/25, 28%). Whilst the CAP guideline for WSI validation in clinical practice helped the widespread adoption of digital pathology, more evidence is required to routinely employ WSI for diagnostic purposes in cytopathology practice. More dedicated validation studies satisfying all SRs and/or GPSs recommended by the CAP are needed to help expedite the use of WSI for primary diagnosis in cytopathology.

Inter- and intraobserver agreement in whole-slide digital ThinPrep samples of low-grade squamous lesions of the cervix uteri with known high-risk HPV status: A multicentric international study.

BACKGROUND: High-risk human papilloma virus (HR HPV) testing and liquid-based cytology are used for primary cervical screening. Digital cytology, based on whole-slide scanned samples, is a promising technique for teaching and diagnostic purposes. The aim of our study was to evaluate the interobserver and intraobserver variation in low-grade squamous lesions, HR HPV status bias, and the use of whole-slide scanned digital cervical cytology slides. METHODS: Fifteen expert cytopathologists evaluated 71 digitalized ThinPrep slides (31 atypical squamous cells of undetermined significance [ASC-US], 21 negative for intraepithelial lesion or malignancy, and 19 low-grade squamous intraepithelial lesion cases). HR HPV data were accessible only in the second round. RESULTS: In interobserver analysis, Kendall's coefficient of concordance was 0.52 in the first round and 0.58 in the second round. Fleiss' kappa values were 0.29 in the first round and 0.31 in the second round. In the ASC-US category, Fleiss kappa increased from 0.19 to 0.22 in the second round and the increase was even higher expressed by Kendall's coefficient: from 0.42 to 0.52. In intraobserver analysis, personal scores were higher in the second round. CONCLUSIONS: The interobserver and intraobserver variability in low-grade squamous lesions was within fair agreement values in the present study, in line with previous works. The comparison of two rounds showed that expert cytopathologists are generally unbiased by the knowledge of HR HPV data, but that being informed of the HR HPV status leads to a better agreement. Stain quality and back discomfort were highlighted as factors affecting digital cytopathology use.

Multicentre Evaluation of Hepika Test Clinical Accuracy in Diagnosing HPV-Induced Cancer and Precancerous Lesions of the Uterine Cervix.

OBJECTIVE: To evaluate the clinical accuracy of Hepika test to identify cancer/precancerous lesions of the uterine cervix. MATERIALS AND METHODS: A multicentre retrospective study was carried out in 2018 and included 330 liquid-based cytology samples from three Italian centres of women aged 25-64 who had been tested for the human papillomavirus (HPV) and whose histology or follow-up outcome was known. Hepika is an enzyme-linked immunosorbent assay (ELISA) targeting the protein complexes E6#p53 and E7#pRb. After excluding samples without sufficient residual material, the clinical accuracy of Hepika test was evaluated in 274 samples: adenocarcinoma (ADC) (4), squamous cell carcinoma (SCC) (7), adenocarcinoma in situ (AIS) (1), cervical intraepithelial neoplasia (CIN) grade 3 (60), CIN2 (51), CIN1 (34), and negative histology (117). Association, sensitivity, and specificity for carcinoma, CIN3+ and CIN2+ are reported. RESULTS: Positive Hepika test was associated with a high probability of carcinoma (odds ratio (DOR) = 33.68, 95% confidence interval (CI) 7.0-163.1); sensitivity was 81.8%, specificity, 88.2%. A positive Hepika test showed a weaker association with CIN3+ lesions (DOR = 3.5; 95% CI 1.75-6.99) and lower sensitivity (27.8%). CONCLUSION: The Hepika test was found to be an accurate biomarker for HPV-induced cervical carcinoma. Population-based prospective studies are needed to confirm the clinical usefulness of the Hepika test in the differential diagnosis of HPV-induced invasive lesions.

Recommendations of the European Advisory Committee of Cytotechnology and European Federation of Cytology Societies for Training and Education of Cytotechnologists in Europe.

BACKGROUND: Faced with changes in cytodiagnostics, cervical cancer screening programs, the introduction and application of new methods, the cytotechnological educational program requires the necessary changes and additions. Insufficient, uneven as well as inaccessible education of cytotechnologists in European countries was the basis for making these recommendations. SUMMARY: The results of previous research and publications related to the currently available education of cytotechnologists in Europe, the needs and suggestions were given by the European Advisory Committee of Cytotechnology (EACC) and European Federation of Cytology Societies (EFCS) for optimal education of future generations of cytotechnologists were used in the preparation of these recommendations. The EACC and EFCS propose a 1-year education and training program divided into 3 modules: gynecological, nongynecological exfoliative, and fine-needle aspiration cytology. Training programs should be organized by an accredited university, preferably a combination of internal education in a cytology laboratory and theoretical education at the university. Cytopathologists and cytotechnologists with at least 5 years of work experience in cytodiagnostics should participate in education. Upon completion of the training program, the EACC and EFCS propose an official name: EFCS certified cytotechnologist. Key Messages: The EACC and EFCS believe that it is extremely important that these recommendations are recognized and implemented by institutions that provide education for cytotechnologists so that they can meet the growing requirements of the profession with their acquired knowledge and competencies.

Non-human papilloma virus associated adenocarcinomas of the cervix uteri. Cytologic features and diagnostic agreement using whole slide digital cytology imaging.

BACKGROUND: Non-Human Papilloma Virus associated adenocarcinomas (NHPVAs) are uncommon tumors of the cervix uteri which often show a deceptive morphology. Therefore, their diagnostic assessment may be challenging. Slide digital cytology imaging may be an useful tool to improve cytological diagnostic accuracy. However, this novel technology has not been applied to NHPVAs associated cytologies yet. METHODS: The study included 31 whole slide digital cytology cases from 10 women with a proven histological diagnosis of NHPVA. As a control group, three further digital slides, from two women with a histological diagnosis of squamous intraepithelial lesion (SIL), were included. The digitally scanned cytological slides were revised to assess the concordance rate among three observers and to find out the most relevant NHPVA cytological criteria. RESULTS: Overall diagnostic agreement between observers was 67.60% (K = 0.50; P < 0.0001). At the consensus diagnosis 34 cases were re-classified as at least suspicious for glandular lesion (n = 24), SIL (n = 2) and negative (n = 8). The most relevant cytologic features for atypical glandular cells or adenocarcinoma at consensus were evident nucleoli, nuclear overlapping and atypical enlarged nuclei. CONCLUSIONS: The diagnosis of NHPVA in digital cytology is feasible using criteria which are also used in conventional microscopy. Our study shows a moderate agreement for the cytological diagnosis of NHPVAs using whole slide digital cytology approach. These results are discussed taking into account the most relevant differential diagnostic issues.

Graft-versus-host disease (GvHD) of the tongue and of the oral cavity: a large retrospective study.

Graft-versus-host disease (GvHD) causes severe mucositis, impairs feeding and favors infection. The objective of this study was to identify the impact of GvHD in the oral cavity. We reviewed all consecutive patients who developed oral GvHD after HSCT. The study period was over 14 years. 53 patients were identified. M/F = 1.4; median age was 48.6 years; the median follow-up was for up to 3 years and 6 months. Conditioning regimens included several drugs (e.g., busulfan, cyclophosphamide and fludarabine). In 11 cases, radiotherapy (RT) was also used. Patients treated with RT were more likely to have tooth decay requiring fillings (p = 0.029), to need canal root interventions (p = 0.005) and to have tartar requiring oral hygiene interventions (p = 0.011). Patients with a lymphoma diagnosis were more likely to develop perioral scleroderma and chronic oral GvHD (cGvHD) (p = 0.045). Oral acute GvHD (aGvHD) was seen in 26 patients (49.1%). 21 (39.6%) patients developed cGvHD. GvHD of the tongue was seen in 21 (40%) patients. Oral mucositis was seen in only 5 patients (9.4%). Conditioning regimens with RT are more likely to induce oral aGvHD. The tongue is often affected by GvHD.

Prediction of histological grade of endometrial cancer by means of MRI.

OBJECTIVES: To evaluate the ability of MRI in predicting histological grade of endometrial cancer (EC). METHODS: IRB-approved retrospective study; requirement for informed consent was waived. 90 patients with histologically proven EC who underwent preoperative MRI and surgery at our Institution between Sept2011 and Nov2016 were included. Myometrial invasion (50%) was assessed. Neoplasm and uterus volumes were estimated according to the ellipsoid formula; neoplasm/uterus volume ratio (N/U) was calculated. ADC maps were generated and histogram analysis was performed using commercially available software. MRI parameters were compared with the definitive histological grade (G1 = 28 patients, G2 = 29, G3 = 33) using ANOVA and Tukey-Kramer tests. RESULTS: Deep myometrial invasion was significantly more frequent in G2-G3 lesions than in G1 ones (p < 0,005). N/U ratio was significantly higher for high-grade neoplasms (mean 0,08 for G1, 0,16 for G2 and 0,21 in G3; P = 0,002 for G1 vs. G2-G3); a cut off value of 0,13 enabled to distinguish G1 from G2-G3 lesions with 50% sensibility and 89% specificity. ADC values didn't show any statistically significant correlation with tumour grade. CONCLUSIONS: N/U ratio >0.13 and deep myometrial invasion are significantly correlated with high grade EC, whereas ADC values are not useful for predicting EC grade.

Interobserver reproducibility of cytologic p16INK4a /Ki-67 dual immunostaining in human papillomavirus-positive women.

BACKGROUND: The accumulation of cyclin-dependent kinase inhibitor 2A (p16ink4a ) protein in a cell is associated with neoplastic progression in precancerous cervical lesions. Dual staining for p16ink4a and Ki-67 has been proposed as a triage test in cervical cancer screening for women who test positive for human papillomavirus DNA. In this study, interobserver reproducibility of the interpretation of this test was assessed. METHODS: Forty-two immunostained, liquid-based cytology slides were divided into 2 sets and were interpreted by 17 to 21 readers from 9 different laboratories, yielding a total of 816 reports. Immunostaining results were classified as positive, negative, inconclusive, or inadequate. After evaluation of the first set of slides and before circulation of the second set, the results were discussed in a plenary meeting. The 10 slides with the most discordant results were evaluated again by selected expert cytopathologists. RESULTS: The overall κ value was 0.612 (95% confidence interval [CI], 0.523-0.701), it was higher for the positive and negative categories (κ = 0.692 and κ = 0.641, respectively), and it was almost null for the inconclusive category (κ = 0.058). Considering only readers from laboratories with documented experience, the κ value was higher (κ = 0.747; 95% CI, 0.643-0.839) compared with nonexperienced centers (κ = 0.498; 95% CI, 0.388-0.616). The results were similar in both sets of slides (κ = 0.505 [95% CI, 0.358-0.642] and κ = 0.521 [95% CI, 0.240-0.698] for the first and second sets, respectively). Reinterpretation of the slides with the most discordant results did not provide any improvement (first evaluation, κ = 0.616 [95% CI, 0.384-0.866]; second evaluation, κ = 0.403 [95% CI, 0.182-0.643]). CONCLUSIONS: Dual staining for p16 ink4a and Ki-67 demonstrated good reproducibility, confirming its robustness, which is a necessary prerequisite for its adoption as a triage test in cervical cancer screening programs that use human papillomavirus DNA as a primary test. Cancer Cytopathol 2017;125:212-220. © 2016 American Cancer Society.

Platelet gel: a new therapeutic tool with great potential.

Chronic wounds, such as diabetic foot ulcers, represent a serious clinical problem for patients and clinicians. Management of these wounds has a strong economic impact worldwide. Complications resulting from injuries are a frequent cause of morbidity and mortality. Chronic wounds lead to infections, painful dressings and prolonged hospitalisation. This results in poor patient Quality of Life and in high healthcare costs. Platelet concentrates (PC) are defined as autologous or allogeneic platelet derivatives with a platelet concentration higher than baseline. PC are widely used in different areas of Regenerative Medicine in order to enhance wound healing processes; they include platelet-rich plasma (PRP), platelet gel (PG), platelet-rich fibrin (PRF), serum eye drops (E-S), and PRP eye drops (E-PRP). This review highlights the use of platelet-rich plasma (PRP) and platelet gel (PG) preparation for clinical use.

Intravascular large B-cell lymphoma associated with silicone breast implant, HLA-DRB1*11:01, and HLA-DQB1*03:01 manifesting as macrophage activation syndrome and with severe neurological symptoms: a case report.

BACKGROUND: Silicone implants have been successfully used for breast augmentation and reconstruction in millions of women worldwide. The reaction to the silicone implant is highly variable; it can lead to local inflammatory symptoms, and sometimes to systemic symptoms and disease. Over 80 cases of anaplastic lymphoma kinase-negative anaplastic large cell lymphoma have been reported in patients with silicone breast implants and have been accepted as a new clinical entity. To the best of our knowledge, an intravascular large B-cell lymphoma associated with a silicone breast implant has not been reported previously. CASE PRESENTATION: A 48-year-old Caucasian woman who presented with high fever was found to have splenomegaly on physical examination. A laboratory diagnosis revealed pancytopenia, hypertriglyceridemia, and hyperferritinemia. She developed signs of altered sensorium, hemiparesis, aphasia, and cauda equina syndrome. On further evaluation, she fulfilled the necessary five out of eight criteria for diagnosis of macrophage activation syndrome/hemophagocytic lymphohistiocytosis. Dexamethasone administration was followed by prompt improvement; however, 3 days later she again manifested high fever, which persisted despite administration of immunoglobulin and cyclosporine A. Her silicone breast implant was considered a possible contributor to her macrophage activation syndrome and was therefore removed. A histological examination of the capsule tissue showed an extensive lymphohistiocytic/giant cell foreign body reaction suggestive of autoimmune/inflammatory syndrome induced by adjuvants. However, the histological examination unexpectedly also revealed an intravascular large B-cell lymphoma. CONCLUSIONS: The genetic background of our patient with silicone breast implants might have predisposed her to three rare and difficult to diagnose syndromes/diseases: macrophage activation syndrome/hemophagocytic lymphohistiocytosis, autoimmune/inflammatory syndrome induced by adjuvants, and intravascular large B-cell lymphoma. The simultaneous manifestation of all three syndromes suggests causal interrelationships. Human leukocyte antigen testing in all women who undergo silicon breast implantation could in the future enable us to better evaluate the risk of potential side effects.

Pap-tests with non-hyperchromatic dyskariosis are often associated with squamous intraepithelial lesions of the cervix uteri with eosinophilic features.

BACKGROUND: Squamous intraepithelial lesions of the cervix uteri with eosinophilic features (eosinophilic dysplasia, ED) are a peculiar type of dysplasia with metaplastic phenotype which was described in histological specimens. The cytological features of these lesions have not been studied yet. METHODS: Histological samples from 66 women with features of ED and positive p16(INK4a) staining were included in the study. Within the previous year, all women had at least one pap-test, whose features were recorded and compared with 31 control samples with high-grade dysplasia of usual type. RESULTS: The previous pap-test showed high-grade dysplastic cells with non-hyperchromatic nuclei in 56/66 (84.8%) cases and metaplastic features in 60/66 (90.9%) cases. Conversely, the dysplastic cells of the usual lesions showed non-hyperchromatic nuclei in 6/31 (19.4%) and metaplastic features in 4/31 (12.9%) cases. Statistical analysis showed significant differences in distribution of the non-hyperchromatic nuclei (P < 0.001), metaplastic features (P < 0.001), presence of both non-hyperchromatic nuclei and metaplastic features (P < 0.001) and usual dysplastic features (P < 0.001) among the study and control groups. CONCLUSIONS: A high-grade squamous intraepithelial lesion with non-hyperchromatic nuclei or metaplastic features is often found in the pap-test previous to the histological diagnosis of ED and may represent the cytologic correlate of this particular type of dysplasia. Diagn. Cytopathol. 2016;44:783-786. © 2016 Wiley Periodicals, Inc.

Healing of a soft tissue wound of the neck and jaw osteoradionecrosis using platelet gel.

AIM: Bone osteoradionecrosis is a serious complication of radiation treatment. Current treatment approaches are not curative and treatment response is often poor leading to high social and healthcare costs. CASE REPORT: We report on the first case of osteoradionecrosis with successful restitutio ab integro by repeated administration of platelet gel (PLT-gel) and surgery in a critically ill patient. The administration of PLT-gel during a severe septic episode helped regeneration of bone and soft tissues, shortening the hospital stay of the patient. It was also noted that following applications of PLT-gel, both the use of morphine and the numbers of infective episodes were reduced. CONCLUSION: Additional studies are needed to confirm the promising effect of PLT-gel for the treatment of osteoradionecrosis.

Randomized Trial Comparing R-CHOP Versus High-Dose Sequential Chemotherapy in High-Risk Patients With Diffuse Large B-Cell Lymphomas.

Purpose The benefit of high-dose chemotherapy with autologous stem-cell transplantation (ASCT) as first-line treatment in patients with diffuse large B-cell lymphomas is still a matter of debate. To address this point, we designed a randomized phase III trial to compare rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-14 (eight cycles) with rituximab plus high-dose sequential chemotherapy (R-HDS) with ASCT. Patients and Methods From June 2005 to June 2011, 246 high-risk patients with a high-intermediate (56%) or high (44%) International Prognostic Index score were randomly assigned to the R-CHOP or R-HDS arm, and 235 were analyzed by intent to treat. The primary efficacy end point of the study was 3-year event-free survival, and results were analyzed on an intent-to-treat basis. Results Clinical response (complete response, 78% v 76%; partial response, 5% v 9%) and failures (no response, 15% v 11%; and early treatment-related mortality, 2% v 3%) were similar after R-CHOP versus R-HDS, respectively. After a median follow-up of 5 years, the 3-year event-free survival was 62% versus 65% ( P = .83). At 3 years, compared with the R-CHOP arm, the R-HDS arm had better disease-free survival (79% v 91%, respectively; P = .034), but this subsequently vanished because of late-occurring treatment-related deaths. No difference was detected in terms of progression-free survival (65% v 75%, respectively; P = .12), or overall survival (74% v 77%, respectively; P = .64). Significantly higher hematologic toxicity ( P < .001) and more infectious complications ( P < .001) were observed in the R-HDS arm. Conclusion In this study, front-line intensive R-HDS chemotherapy with ASCT did not improve the outcome of high-risk patients with diffuse large B-cell lymphomas.

Circulating microparticles, protein C, free protein S and endothelial vascular markers in children with sickle cell anaemia.

INTRODUCTION: Circulating microparticles (MP) have been described in sickle cell anaemia (SCA); however, their interaction with endothelial markers remains unclear. We investigated the relationship between MP, protein C (PC), free protein S (PS), nitric oxide (NO), endothelin-1 (ET-1) and adrenomedullin (ADM) in a large cohort of paediatric patients. METHOD: A total of 111 children of African ethnicity with SCA: 51 in steady state; 15 in crises; 30 on hydroxyurea (HU) therapy; 15 on transfusion; 17 controls (HbAA) of similar age/ethnicity. MP were analysed by flow cytometry using: Annexin V (AV), CD61, CD42a, CD62P, CD235a, CD14, CD142 (tissue factor), CD201 (endothelial PC receptor), CD62E, CD36 (TSP-1), CD47 (TSP-1 receptor), CD31 (PECAM), CD144 (VE-cadherin). Protein C, free PS, NO, pro-ADM and C-terminal ET-1 were also measured. RESULTS: Total MP AV was lower in crisis (1.26×10(6) ml(-1); 0.56-2.44×10(6)) and steady state (1.35×10(6) ml(-1); 0.71-3.0×10(6)) compared to transfusion (4.33×10(6) ml(-1); 1.6-9.2×10(6), p<0.01). Protein C levels were significantly lower in crisis (median 0.52 IU ml(-1); interquartile range 0.43-0.62) compared with all other groups: HbAA (0.72 IU ml(-1); 0.66-0.82, p<0.001); HU (0.67 IU ml(-1); 0.58-0.77, p<0.001); steady state (0.63 IU ml(-1); 0.54-0.70, p<0.05) and transfusion (0.60 IU ml(-1); 0.54-0.70, p<0.05). In addition, levels were significantly reduced in steady state (0.63 IU ml(-1); 0.54-0.70) compared with HbAA (0.72 IU ml(-1); 0.66-0.80, p<0.01). PS levels were significantly higher in HbAA (0.85 IU ml(-1); 0.72-0.97) compared with crisis (0.49 IU ml(-1); 0.42-0.64, p<0.001), HU (0.65 IU ml(-1); 0.56-0.74, p<0.01) and transfusion (0.59 IU ml(-1); 0.47-0.71, p<0.01). There was also a significant difference in crisis patients compared with steady state (0.49 IU ml(-1); 0.42-0.64 vs. 0.68 IU ml(-1); 0.58-0.79, p<0.05). There was high correlation (R>0.9, p<0.05) between total numbers of AV-positive MP (MP AV) and platelet MP expressing non-activation platelet markers. There was a lower correlation between MP AV and MP CD62P (R=0.73, p<0.05) (platelet activation marker), and also a lower correlation between percentage of MP expressing CD201 (%MP CD201) and %MP CD14 (R=0.627, p<0.001). %MP CD201 was higher in crisis (11.6%) compared with HbAA (3.2%, p<0.05); %MP CD144 was higher in crisis (7.6%) compared with transfusion (2.1%, p<0.05); %CD14 (0.77%) was higher in crisis compared with transfusion (0.0%, p<0.05) and steady state (0.0%, p<0.01); MP CD14 was detectable in a higher number of samples (92%) in crisis compared with the rest (40%); %MP CD235a was higher in crisis (17.9%) compared with transfusion (8.9%), HU (8.7%) and steady state (9.9%, p<0.05); %CD62E did not differ significantly across the groups and CD142 was undetectable. Pro-ADM levels were raised in chest crisis: 0.38 nmol L(-1) (0.31-0.49) versus steady state: 0.27 nmol L(-1) (0.25-0.32; p<0.01) and control: 0.28 nmol L(-1) (0.27-0.31; p<0.01). CT-proET-1 levels were reduced in patients on HU therapy: 43.6 pmol L(-1) (12.6-49.6) versus control: 55.1 pmol L(-1) (45.2-63.9; p<0.05). NO levels were significantly lower in chest crisis (19.3 mmol L(-1) plasma; 10.7-19.9) compared with HU (22.2 mmol L(-1) plasma; 18.3-28.4; p<0.05), and HbSC (30.6 mmol L(-1) plasma; 20.8-39.5; p<0.05) and approach significance when compared with steady state (22.5mmol L(-1) plasma; 16.9-28.2; p=0.07). CONCLUSION: Protein C and free PS are reduced in crisis with lower numbers of platelet MP and higher percentage of markers of endothelial damage and of red cell origin. During chest crisis, ADM and ET-1 were elevated suggesting a role for therapy inhibiting ET-1 in chest crisis.

The predictive value of human papillomavirus testing for the outcome of patients conservatively treated for stage IA squamous cell cervical carcinoma.

BACKGROUND: Although it is hypothesised that human papillomavirus (HPV) testing may have a role in surveillance of patients conservatively treated for stage IA squamous cell cervical carcinoma, research on this topic has been minimal. OBJECTIVES: To determine: (1) the changes in HPV test result from treatment onward; (2) the time to viral clearance; and (3) the negative predictive value (NPV) and positive predictive value (PPV) of HPV test result for the detection of CIN2 or worse (CIN2+) during follow-up. STUDY DESIGN: In a multicentre retrospective follow-up study of a consecutive series (1997-2009) of 91 patients, longitudinal outcome measures were estimated as cumulative probabilities using the Kaplan-Meier method. RESULTS: For patients testing HPV-positive at the first follow-up visit (n=44), the probability of change to negative rose from 0 to 0.78 between 7 and 21 months after treatment. For HPV-negative patients (n=47), the probability of change to positive rose to 0.13 between 9 and 26 months. After a median follow-up of 50 months (range, 2-80), the NPV for CIN2+ was 1.00. The PPV was 0.60 (95% confidence interval, 0.43-0.77) after 26 months. The median time to detection was 5 months. CONCLUSIONS: If adequately confirmed, these findings would indicate that HPV testing is capable to identify the patients who have had their lesions fully removed, and would make it possible to focus follow-up efforts on a subset of patients at high risk of residual or progressive disease.

Consensus diagnostic histopathological criteria for acute gastrointestinal graft versus host disease improve interobserver reproducibility.

Graft versus host disease (GvHD) is a clinically important complication after allogeneic hematopoietic stem cell transplantation (HSCT). Its diagnosis relies on clinical and histopathological findings. In order to evaluate and improve inter-institutional diagnostic agreement on histological diagnosis and grading of acute gastrointestinal GvHD, we conducted a round robin test, which included 33 biopsies from 23 patients after HSCT. Five pathologists from different institutions independently evaluated the original sections from the biopsies submitted for diagnosis. Based on their results, consensus qualitative criteria for the assessment of typical histological features of GvHD (e.g., apoptosis, crypt destruction, mucosa denudation) were proposed, including detailed descriptions as well as histological images. In a second round robin test with involvement of the same pathologists, the reproducibility of both diagnosis and grading had improved. Remaining differences were mostly related to differential diagnostic considerations, including viral infection or toxic side effects of medication, which should be resolved by integrating histopathological findings with proper clinical information.