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. ResultsClinical 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. ConclusionIn 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.J Clin Oncol 34.

p16 is a tumor suppressor gene that plays a central role in the regulation of the cell cycle. In squamous cervical cancers, overexpression of p16 is induced by HPV and associated with the carcinogenesis of cervical epithelia. The aim of this study was to determine whether immunostaining of p16 is useful in detecting adenocarcinomas of the cervix uteri in histologic and cytologic routine specimens. A total of 45 surgical specimens, including 18 cases of invasive carcinoma, 8 cases of adenocarcinoma in situ, 4 cases of endocervical glandular atypia (cervical glandular intraepithelial neoplasia), and 15 reactive lesions of the endocervical glands were immunostained using a specific anti-human p16 monoclonal antibody (clone E6H4, mtm laboratories AG, Heidelberg, Germany). Furthermore, immunocytochemical analysis was performed on 10 preoperative ThinPrep cytologic samples with abnormal glandular cells and compared with the human papillomavirus status as assessed with the Hybrid Capture II test. p16 was detected immunohistochemically in all 26 cases of adenocarcinoma of the cervix uteri, including 18 invasive and 8 in situ carcinomas. Only a focal expression was evidenced in the four specimens with endocervical glandular atypia, and no reaction was found in reactive lesions. Also, the immunocytochemical analysis on the 10 ThinPrep specimens evidenced a strong expression of p16 in neoplastic endocervical cells. In all cases this was associated with a high-risk HPV-positive typing. p16 is a useful marker for the detection of the adenocarcinoma of the cervix uteri and its precursors. The immunocytochemical detection on ThinPrep specimens may contribute to an early detection of endocervical lesions.

The aim of the study was to evaluate the immunohistochemical expression of p16INK4a as a marker of progression risk in low-grade dysplastic lesions of the cervix uteri. p16INK4a immunohistochemistry was performed on 32 CIN1 with proven spontaneous regression of the lesion in the follow-up (group A), 31 (group B) with progression to CIN3 and 33 (group C) that were randomly chosen irrespective of the natural history of the lesion. p16INK4a staining pattern was scored as negative (less than 5% cells in the lower third of dysplastic epithelium stained), as focally positive (< or = 25%) and as diffuse positive (> 25%). A diffuse staining pattern was detected in 43.8% of CIN1 of group A, 74.2% of group B and 56.3% of group C. No p16INK4a staining was detected in 31.3% and 12.9% CIN1 lesions of groups A and B, respectively. Overall, 71.4% and 37.8% of p16INK4a-negative and diffusely positive CIN1 had regressed at follow-up, whereas 28.6% and 62.2% negative and diffusely positive CIN1 were progressed to CIN3, respectively (P < 0.05). All CIN3 lesions analyzed during follow-up of group B were diffusely stained for p16INK4a. Although p16INK4a may be expressed in low-grade squamous lesions that undergo spontaneous regression, in this study, CIN1 cases with diffuse p16INK4a staining had a significantly higher tendency to progress to a high-grade lesion than p16INK4a-negative cases. p16INK4a may have the potential to support the interpretation of low-grade dysplastic lesions of the cervix uteri.

IntroductionCirculating 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.MethodA 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.ResultsTotal MP AV was lower in crisis (1.26×106 ml−1; 0.56–2.44×106) and steady state (1.35×106 ml−1; 0.71–3.0×106) compared to transfusion (4.33×106 ml−1; 1.6–9.2×106, 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....

As only a minority of low-grade dysplastic lesions of the cervix uteri will eventually progress to carcinoma, predicting the behavior of these lesions could be of high value in clinical practice. The aim of the study was to evaluate p16 ink4a and L1 as immunohistochemical markers of the biologic potentiality of low-grade dysplasia of the uterine cervix. The study included 38 conization specimens with coexisting cervical intraepithelial neoplasia grade 1 (CIN1) and 3 (CIN3) (group A) and 28 punch biopsies from women with CIN1 and proven spontaneous regression in the follow-up (group B). In group A, all CIN3 were p16 ink4a positive (p16+) and L1 negative (L1-). The CIN1 of this group were p16+L1- and p16+L1+ in 68.42% and 31.57%, respectively. No other expression pattern was found in this group. In group B, the p16+L1-, p16+L1+, p16-L1+, and p16-L1- patterns were found in 3.57%, 25%, 14.29%, and 57.14%, respectively. Overall, 96.29% p16+L1- CIN1 were found in group A, whereas all the p16-L1+ and p16-L1- CIN1 were found in group B. A significant difference between staining pattern distributions of group A and B was observed (P<0.0001). The results of the study show that p16 ink4a and L1 immunohistochemistry can be helpful for estimating the biologic potentiality of low-grade squamous cervical lesions. Particularly in cases in which the grade of the lesion is morphologically difficult to assess, the p16/L1 expression pattern could be useful for planning the clinical management of these women.

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The aim of the study was to assess the value of liquid-based urinary cytology as a tool to perform uCyt+ and Multicolour-FISH in patients under follow-up after urothelial cancer. Therefore, standard cytology was compared to liquid-based cytology with the addition of the uCyt+ test, which traces the three monoclonal antibodies M344, LDQ10 and 19A211 in exfoliated urothelial cells; and Multicolour-FISH (including centromere-specific probes for chromosomes 3, 7, 17 and a locus-specific probe for 9p21/p16) performed on thin-layer specimens. UCyt+ showed an overall sensitivity of 86.2% and cytology of 45.0%. Overall sensitivity of both the tests combined was 90%. Sensitivity of Multicolour-FISH was 96.4%. All conventional cytology diagnoses were confirmed by liquid-based cytology. Liquid-based cytology is a valid tool for the performance of adjunctive analyses, such as uCyt+ and Multicolour-FISH, on residual cellular material.

We report on 2 phenotypic sisters, one with 46,XY; the other with 46,XX. The 2 girls had similar related internal malformations, including agonadism, hypoplasia of the right pulmonary artery, hypoplasia of the right lung, isolated dextrocardia with complex vitium cordis, and diaphragmatic hernia (only sib 1) or omphalocele (only sib 2). This combination of malformations did not fit into any of the previously described syndromes. For this syndrome we suggest the acronym PAGOD ([hypoplasia of the] pulmo, and pulmonary artery, agonadism, omphalocele/diaphragmatic defect, dextrocardia). The occurrence of a basically similar set of malformations in 2 unlike sex is interpreted as evidence for autosomal recessive inheritance. The different gonosomal status excludes the Y chromosome as a responsible factor. The peculiar finding of a 46,XX sex chromosome constitution combined with agonadism and an intact urogenitral tract emphasizes the concept of secondary regression of Wolffian and Müllerian structures. The associated malformations of mesodermal structures can be interpreted as midline defects. We suggest that, from the developmental field perspective, secondary regression of midline structures including the gonadal anlage explains the pathogenesis reasonably well.