A 3-year interval is too short for re-screening women testing negative for human papillomavirus: a population-based cohort study.

OBJECTIVE: To compare the results from an initial negative human papillomavirus (HPV) test with re-screening after 3 years in women attending two HPV-based screening programmes. DESIGN: Population-based cohort study. SETTING: Two cervical service screening programmes in Italy. POPULATION: Women aged 25-64 years invited to screening from April 2009 to October 2015. METHODS: Eligible women were invited to undergo an HPV test. Those with a negative HPV test went on to the next screening round 3 years later. Cytology triage was performed for HPV+ (HPV by Hybrid Capture 2) samples, with immediate colposcopy (if abnormal) and HPV re-testing 1 year later (if negative). MAIN OUTCOME MEASURES: Participation rate, positivity at HPV and at triage, referral rate to colposcopy, positive predictive value for cervical intraepithelial neoplasia grade 2+ (CIN2+) at colposcopy, and detection rate for CIN2+. RESULTS: We present the results from 48 751 women at the first screening and 22 000 women at re-screening 3 years later. The response rate was slightly higher at the second screening (74.5 versus 72.1% at the first screening; referral rate, RR 1.11; 95% confidence interval, 95% CI, 1.07-1.14). Compared with the first screening, we observed a significant reduction at the second screening in terms of HPV positivity (RR 0.55, 95% CI 0.51-0.60), referral rate to colposcopy (RR 0.47, 95% CI 0.41-0.53), CIN2+ detection rate (RR 0.24, 95% CI 0.13-0.39), and positive predictive value (PPV) for CIN2+ at colposcopy (RR 0.51, 95% CI 0.29-0.87). CONCLUSIONS: The very low frequency of disease and inadequate PPV at colposcopy indicate that a 3-year interval after a negative HPV test is too short. TWEETABLE ABSTRACT: Three years after a negative HPV the frequency of cervical disease is so low that re-screening is inefficient.

Rasch-built Overall Disability Scale for patients with chemotherapy-induced peripheral neuropathy (CIPN-R-ODS).

Chemotherapy-induced peripheral neuropathy (CIPN) is a common neurological side-effect of cancer treatment and may lead to declines in patients' daily functioning and quality of life. To date, there are no modern clinimetrically well-evaluated outcome measures available to assess disability in CIPN patients. The objective of the study was to develop an interval-weighted scale to capture activity limitations and participation restrictions in CIPN patients using the Rasch methodology and to determine its validity and reliability properties. A preliminary Rasch-built Overall Disability Scale (pre-R-ODS) comprising 146 items was assessed twice (interval: 2-3 weeks; test-retest reliability) in 281 CIPN patients with a stable clinical condition. The obtained data were subjected to Rasch analyses to determine whether model expectations would be met, and if necessarily, adaptations were made to obtain proper model fit (internal validity). External validity was obtained by correlating the CIPN-R-ODS with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) neuropathy scales and the Pain-Intensity Numeric-Rating-Scale (PI-NRS). The preliminary R-ODS did not meet Rasch model's expectations. Items displaying misfit statistics, disordered thresholds, item bias or local dependency were systematically removed. The final CIPN-R-ODS consisting of 28 items fulfilled all the model's expectations with proper validity and reliability, and was unidimensional. The final CIPN-R-ODS is a Rasch-built disease-specific, interval measure suitable to detect disability in CIPN patients and bypasses the shortcomings of classical test theory ordinal-based measures. Its use is recommended in future clinical trials in CIPN.

Ultrasound assessment of oxaliplatin-induced neuropathy and correlations with neurophysiologic findings.

BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy is a major adverse effect of oxaliplatin (OXL) treatment. Whereas neurophysiologic study is commonly used to assess the occurrence and severity of polyneuropathies, ultrasound (US) analysis of the peripheral nerves, an emerging technique in the study of peripheral nerve diseases, has never been used in chemotherapy-induced peripheral neuropathy. PATIENTS AND METHODS: Fifteen patients (four women; 11 men; mean age, 60.1 ± 10.6 years; median, 62; range, 37-75) with colorectal cancer treated with OXL-based treatment have been clinically and neurophysiologically evaluated before and after OXL therapy. At the end of chemotherapy, all patients underwent also nerve US study at four limbs, and the findings correlated with clinical and neurophysiologic measures. RESULTS: Clinical and neurophysiological evaluation showed that 13 of 15 (86.7%) patients developed sensory axonal neuropathy, 10 of whom severe (two or more sensory nerve action potential amplitude absent and the other amplitudes decreased of ≥50%). Nerve US did not reveal decreased cross-sectional area (CSA), a reported finding in axonal neuropathies. Instead increased CSA at entrapment sites (median nerve at wrist and ulnar nerve at elbow) was found in 09/15 (60%) of patients. DISCUSSION: Sensory axonal neuropathy is a very common complication of OXL therapy, affecting almost 90% of patients. US findings of enlargement of median and ulnar nerves, mostly at entrapment sites, in patients with no history or symptoms of neuropathies at recruitment, and no neurophysiologic evidence of entrapment, may be expression of increased, OXL-induced, nerve susceptibility to mechanical damage. An ongoing prospective study will help clarify these findings.

Advanced age and liability to oxaliplatin-induced peripheral neuropathy: post hoc analysis of a prospective study.

BACKGROUND AND PURPOSE: The aim of this post hoc analysis of data extracted from a prospective, multicenter study is to test in a large homogenous population of chemotherapy-naïve patients with colorectal cancer (CRC) treated with oxaliplatin (OXA)-based chemotherapy whether advanced age increases the risk of developing OXA-induced peripheral neuropathy (OXAIPN). METHODS: One-hundred and forty-five patients with CRC, without other significant co-morbidities predisposing to peripheral neuropathy, were divided according to their age into two groups: patients aged between 50 and 68 years (group I, n = 75); and patients aged ≥ 69 years (group II, n = 70). Patients were prospectively monitored at baseline and followed-up during chemotherapy using the motor and neurosensory National Cancer Institute Common Toxicity criteria, the clinical version of the Total Neuropathy Score and neurophysiology. The incidence and severity of both the acute and cumulative OXAIPN was thoroughly determined and then compared between age groups. RESULTS: No statistically significant difference was observed in the incidence of both the acute (n = 64/75 vs. 56/70; P = 0.510) and cumulative OXAIPN (n = 51/75 vs. 49/70; P = 0.858) between age groups. The severity of OXAIPN was also similar between age groups. In line with the clinical data, the neurophysiological results between age groups were also comparable. CONCLUSION: The results of this study indicate that advanced age does not seem to represent a significant risk factor of OXAIPN in patients with CRC without any other significant co-morbidities.

Presence of NGF and its receptor TrkA in degenerative lumbar facet joint specimens.

In a preliminary study, the recurrent presence of nervous terminations was demonstrated with optical microscopy in several slides of degenerative lumbar facet joints and surrounding soft tissues. The purpose of this study was to prove the presence of NGF (nerve growth factor) and its receptor TrkA (tyrosine kinase receptor) with immunofluorescence. The peri/articular tissues were harvested from the lumbar facet joints of ten patients surgically treated for degenerative diseases. There were seven females (one bilateral) and two males whose mean age at surgery was 72 years (range, 67-80 years). The affected levels were L3-L4 in two cases and L4-L5 in seven cases (one bilateral). All specimens were fixed in formalin, dehydrated and enclosed in paraffin. From each specimen, four slides were obtained. Two slides were employed for the search of NGF: one was treated with specific antibodies and marked with FITC (fluorescein isothiocyanate conjugated), and the second slide was for control purposes. It was exposed to FITC, but without prior exposure to the specific antibody. The same procedure was repeated to obtain on two more slides, to repeat the search for Trka with specific antibodies. All the slides were finally studied on a fluoromicroscope. The analysis of these specimens revealed the presence of the neurotrophin (NGF) and its own receptor (TrkA) in all cases: the immunohistochemical reaction between the specimens and the specific antibodies marked with FITC was seen under fluoromicroscopy, but in none of the control cases treated with FITC only. NGF is released by mastocytes, fibroblasts and other cell types involved in the inflammatory processes. The level of peripheral NGF is increased in inflammatory processes, while the administration of exogenous NGF has a hyperalgesic effect on rats and produces muscular pain in humans. Furthermore, NGF produces hypersensitization to heat stimulation in humans and mammals in general. There is considerable evidence showing that the system constituted by the NGF and its high-affinity receptor TrkA plays a fundamental role in the molecular processes underlying the main forms of "persistent" pain. This indicates a possible therapeutic area for the antibodies that could block the NGF/TrkA system, in order to modulate the frequency and the duration of the action potential of nociceptive neurons during chronic inflammation. This study demonstrated the presence of NGF and TrkA in specimens collected from degenerative facet joints, suggesting that specific molecules could be used in order to modulate chronic pain in patients with degenerative lumbar spine.

Structural studies on Pax-8 Prd domain/DNA complex.

Pax-8 is a member of the Pax family of transcription factors and is essential in the development of thyroid follicular cells. Pax-8 has two DNA-binding domains: the paired domain and the homeo domain. In this study, a preliminary X-ray diffraction analysis of the mammalian Pax-8 paired domain in complex with the C-site of the thyroglobulin promoter was achieved. The Pax-8 paired domain was crystallized by the hanging-drop vapor-diffusion method in complex with both a blunt-ended 26 bp DNA fragment and with a sticky-ended 24 bp DNA fragment with two additional overhanging bases. Crystallization experiments make clear that the growth of transparent crystals with large dimensions and regular shape is particularly influenced by ionic strength. The crystals of Pax-8 complex with blunt-ended and sticky-ended DNA, diffracted synchrotron radiation to 6.0 and 8.0 A resolution and belongs both to the C centered monoclinic system with cell dimensions: a = 89.88 A, b = 80.05 A, c = 67.73 A, and beta = 124.3 degrees and a = 256.56, b = 69.07, c = 99.32 A, and beta = 98.1 degrees , respectively. Fluorescence experiments suggest that the crystalline disorder, deduced by the poor diffraction, can be attributed to the low homogeneity of the protein-DNA sample. The theoretical comparative model of the Pax-8 paired domain complexed with the C-site of the thyroglobulin promoter shows the probable presence of some specific protein-DNA interactions already observed in other Pax proteins and the important role of the cysteine residues of PAI subdomain in the redox control of the DNA recognition.

HCV-NS3 and IgG-Fc crossreactive IgM in patients with type II mixed cryoglobulinemia and B-cell clonal proliferations.

We demonstrate that in three cases of MC (two with immunocytoma), the IgM-RF+ component of their cryoprecipitated represents the circulating counterpart of the B-cell receptor (BCR) of the monoclonal overexpanded B-cell population. These IgMs were isolated and used to demonstrate a crossreactivity against both hepatitis C virus (HCV) NS3 antigen and the Fc portion of IgG. Epitopes were identified in a fraction of exemplary samples by using epitope excision approach (NS(31250-1334) and IgG Fc(345-355)). The same phenomenon of crossreactivity has been shown to occur in vivo after immunization of a mouse with the NS3(1251-1270) peptide. To verify if the same reaction was also present in MC samples characterized by an oligo/polyclonal B-cell proliferation, IgM crossreactivity was tested in 14 additional samples. Five out of the 14 were reactive against HCV NS3 and 11 out of 14 were reactive against IgG-Fc peptide. The data support the role of HCV NS3 antigen in a subset of patients with MC, whereas the high frequency of the IgG-Fc epitope suggests that these B cells originate from precursors strongly selected for auto-IgG specificity. We suggest that engagement of specific BCRs by NS3 (or NS3-immunocomplex) antigen could explain the prevalence of IgM cryoglobulins in these patients.