Clinical relevance of partial HPV16/18 genotyping in stratifying HPV-positive women attending routine cervical cancer screening: a population-based cohort study.

OBJECTIVE: To evaluate partial HPV16/18 genotyping as a possible biomarker to select women attending HPV-based cervical cancer screening at higher risk to be referred to colposcopy. DESIGN: Population-based cohort study. SETTING: Organised cervical cancer screening programmes (Italy). POPULATION: Women with high-risk HPV infection (period: 2015-2019). METHODS: We analysed the association between partial HPV16/18 genotyping, cytology triage and histologically confirmed diagnosis of high-grade cervical intraepithelial neoplasia (CIN3+ ) lesions. MAIN OUTCOME MEASURES: Detection rate (DR) and positive predictive value (PPV) for histologically confirmed CIN3+ (any episode in the 2 years after baseline); sensitivity for CIN3+ and number of colposcopies needed for lesion detection. RESULTS: The study included 145 437 women screened with HPV testing by the clinically validated COBAS 4800 HPV assay (Roche). Overall, 9601 (6.6%) women were HPV+ at baseline; HPV16 and HPV18 were present in 1865 and 594 samples, respectively. The cumulative (baseline plus 1-year repeat) cytology positivity was 42.8% and high-grade cytology was significantly higher (P < 0.0001) among women with HPV16 infection at baseline (15.2%). The cumulative CIN3+ DR for women with HPV16, HPV18 and other HPV-type infections was 9.8%, 3.4% and 1.8%, respectively. CONCLUSIONS: Partial HPV16 genotyping may play a role in triage, whereas HPV18 seems to behave much more similarly to the other HPV types and does not provide additional stratification. HPV16 genotyping combined with high-grade cytology can be envisaged as a triage biomarker in cervical screening to maximise CIN3+ detection while minimising colposcopy at baseline or 1-year repeat. TWEETABLE ABSTRACT: HPV16 genotyping combined with high-grade cytology can be used as triage biomarker for CIN3+ in HPV-positive women.

Performance of ultra-low-dose CT for the evaluation of coronary calcification: a direct comparison with coronary calcium score.

AIM: To evaluate the diagnostic performance of ultra-low-dose computed tomography (ULDCT) in comparison to standard coronary calcium score (CCS) acquisition for the evaluation of coronary artery calcification (CAC). MATERIALS AND METHODS: Standard CCS acquisition and ULDCT were performed in patients referred for coronary CT angiography for the evaluation of coronary artery disease. CAC in ULDCT was graded subjectively using a four-point scale (from 0, no calcification, to 3, severe calcification) for the complete study and for each individual coronary segment. The summation of all individual coronary segment scores generated an ULDCT total CAC score. ULDCT results were compared to standard Agatston score and sensitivity and specificity of ULDCT were calculated. RESULTS: CCS and ULDCT were performed in 74 patients, with a mean DLP of 77.7 mGy·cm (±12.1) and 9.3 mGy·cm (±0.6), respectively (p<0.001). Coronary calcification was detected in 47 patients (63.5%) in standard CCS acquisition (median Agatston score of 41; interquartile range [IQR]:0263), in comparison to 42 patients (56.8%) in ULDCT (p<0.001). The sensitivity and specificity of the ULDCT total CAC score ≥1 was 80.9% and 85.2%, respectively, with an accuracy of 82.4%. The area under the receiver operating characteristic curve for the presence of CAC was 0.87. CONCLUSION: ULDCT shows good sensitivity, specificity, and overall accuracy for the detection of coronary calcification with a markedly lower radiation dose in comparison to CCS. ULDCT is unlikely to miss coronary calcification in individuals with at least moderate calcium load (Agatston score >100).

A correlational study between signature, writing abilities and decision-making capacity among people with initial cognitive impairment.

BACKGROUND: Some clinical conditions, including dementia, compromise cognitive functions involved in decision-making processes, with repercussions on the ability to subscribe a will. Because of the increasing number of aged people with cognitive impairment there is an acute and growing need for decision-making capacity evidence-based assessment. AIMS: Our study investigates the relationship between writing abilities and cognitive integrity to see if it is possible to make inferences on decision-making capacity through handwriting analysis. We also investigated the relationship between signature ability and cognitive integrity. METHODS: Thirty-six participants with diagnosis of MCI and 38 participants with diagnosis of initial dementia were recruited. For each subject we collected two samples of signature-an actual and a previous one-and an extract of spontaneous writing. Furthermore, we administered a neuropsychological battery to investigate cognitive functions involved in decision-making. RESULTS: We found significant correlations between spontaneous writing indexes and neuropsychological test results. Nonetheless, the index of signature deterioration does not correlate with the level of cognitive decline. DISCUSSION: Our results suggest that a careful analysis of spontaneous writing can be useful to make inferences on decision-making capacity, whereas great caution should be taken in attributing validity to handwritten signature of subjects with MCI or dementia. CONCLUSIONS: The analysis of spontaneous writing can be a reliable aid in cases of retrospective evaluation of cognitive integrity. On the other side, the ability to sign is not an index of cognitive integrity.

When the single matters more than the group: very high false positive rates in single case Voxel Based Morphometry.

Voxel Based Morphometry (VBM) studies typically involve a comparison between groups of individuals; this approach however does not allow inferences to be made at the level of the individual. In recent years, an increasing number of research groups have attempted to overcome this issue by performing single case studies, which involve the comparison between a single subject and a control group. However, the interpretation of the results is problematic; for instance, any significant difference might be driven by individual variability in neuroanatomy rather than the neuropathology of the disease under investigation, or might represent a false positive due to the data being sampled from non-normally distributed populations. The aim of the present investigation was to empirically estimate the likelihood of detecting significant differences in gray matter volume in individuals free from neurological or psychiatric diagnosis. We compared a total of 200 single subjects against a group of 16 controls matched for age and gender, using two independent datasets from the Neuroimaging Informatics Tools and Resources Clearinghouse. We report that the chance of detecting a significant difference in a disease-free individual is much higher than previously expected; for instance, using a standard voxel-wise threshold of p<0.05 (corrected) and an extent threshold of 10 voxels, the likelihood of a single subject showing at least one significant difference is as high as 93.5% for increases and 71% for decreases. We also report that the chance of detecting significant differences was greatest in frontal and temporal cortices and lowest in subcortical regions. The chance of detecting significant differences was inversely related to the degree of smoothing applied to the data, and was higher for unmodulated than modulated data. These results were replicated in the two independent datasets. By providing an empirical estimation of the number of significant increases and decreases to be expected in each cortical and subcortical region in disease-free individuals, the present investigation could inform the interpretation of future single case VBM studies.

Activating c-KIT mutations in a subset of thymic carcinoma and response to different c-KIT inhibitors.

BACKGROUND: To analyze a multi-institutional series of type C thymic carcinomas (TCs) (including neuroendocrine tumors), focusing on the expression and mutations of c-KIT. MATERIALS AND METHODS: Immunohistochemical expression of c-KIT/CD117, p63, CD5 and neuroendocrine markers, as well as mutational analysis of c-KIT exons 9, 11, 13, 14, 17 by direct sequencing of 48 cases of TCs. Immunohistochemical and molecular data were statistically crossed with clinicopathological features. RESULTS: Overall, 29 tumors (60%) expressed CD117, 69% were positive for CD5 and 85% (41 cases) for p63. Neuroendocrine markers stained all six atypical carcinoids and five poorly-differentiated thymic squamous cell carcinomas. Overall, six CD117-positive cases (12.5%) showed c-KIT mutation. No mutation was detected in CD117-negative tumors and carcinoids. All the mutations were found in poorly-differentiated thymic squamous cell carcinomas expressing CD117, CD5, p63 and lacking neuroendocrine markers (6 of 12 cases with these features). Mutations involved exon 11 (four cases: V559A, L576P, Y553N, W557R), exon 9 (E490K) and exon 17 (D820E). CONCLUSIONS: All TCs need an immunohistochemical screening with CD117, while c-KIT mutation analysis is mandatory only in CD117-positive cases, particularly when coexpressing CD5 and p63, lacking neuroendocrine differentiation. The finding of c-KIT mutation can predict efficacy with different c-KIT inhibitors.

Well-differentiated papillary mesothelioma of the epididymis in a man with recurrent haematospermia.

We present a case of well-differentiated papillary mesothelioma of the epididymis occurring in a 60-year-old man who came to urologic consult after recurrent episodes of haematospermia. The patient denied pain, fever and trauma in genitals. Local examination revealed indolent swelling at the right testicle and ecography localised a well-circumscribed nodule at the epididymis tail, measuring 2 cm in greater diameter, with associated haemorrhagic hydrocele. A nodulectomy was performed and the patient is alive with no evidence of disease 17 months following surgery.

Prognostic role of EGFR gene copy number and KRAS mutation in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy.

BACKGROUND: Epidermal growth factor receptor (EGFR), evaluated by immunohistochemistry, has been shown to have prognostic significance in patients with colorectal cancer. Gene copy number (GCN) of EGFR and KRAS status predict response and outcome in patients treated with anti-EGFR therapy, but their prognostic significance in colorectal cancer patients is still unclear. METHODS: We have retrospectively reviewed the baseline EGFR GCN, KRAS status and clinical outcome of 146 locally advanced rectal cancer (LARC) patients treated with preoperative chemoradiotherapy. Pathological response evaluated by Dworak's tumour regression grade (TRG), disease-free survival (DFS) and overall survival (OS) were analysed. RESULTS: Tumour regression grade 4 and TRG3-4 were achieved in 14.4 and 30.8% of the patients respectively. Twenty-nine (19.9%) and 33 patients (19.2%) had an EGFR/nuclei ratio >2.9 and CEP7 polisomy >50% respectively; 28 patients (19.2%) had a KRAS mutation. Neither EGFR GCN nor KRAS status was statistically correlated to TRG. 5-year DFS and OS were 63.3 and 71.5%, respectively, and no significant relation with EGFR GCN or KRAS status was found. CONCLUSION: Our data show that EGFR GCN and KRAS status are not prognostic factors in LARC treated with preoperative chemoradiation.

Epidermal growth factor receptor gene copy number, K-ras mutation and pathological response to preoperative cetuximab, 5-FU and radiation therapy in locally advanced rectal cancer.

BACKGROUND: Cetuximab improves activity of chemotherapy in metastatic colorectal cancer (mCRC). Gene copy number (GCN) of epidermal growth factor receptor (EGFR) has been suggested to be a predictive factor of response to cetuximab in patients (pts) with mCRC; on the contrary, K-ras mutation has been associated with cetuximab resistance. PATIENTS AND METHODS: We have conducted a phase II study with cetuximab administered weekly for 3 weeks as single agent and then with 5-fluorouracil and radiation therapy as neo-adjuvant treatment for locally advanced rectal cancer (LARC). EGFR immunohistochemistry expression, EGFR GCN and K-ras mutation were evaluated on diagnostic tumor biopsy. Dworak's tumor regression grade (TRG) was evaluated on surgical specimens. RESULTS: Forty pts have been treated; 39 pts are assessable. TRG 3 and 4 were achieved in nine (23.1%) and three pts (7.7%) respectively; TRG 3-4 rate was 55% and 5.3% in case of high and low GCN, respectively (P 0.0016). Pts with K-ras mutated tumors had lower rate of high TRG: 11% versus 36.7% (P 0.12). In pts with wild-type K-ras, TRG 3-4 rate was 58.8% versus 7.7% in case of high or low GCN, respectively (P 0.0012). CONCLUSIONS: In pts with LARC, EGFR GCN is predictive of high TRG to cetuximab plus 5-FU radiotherapy. Moreover, our data suggest that a wild-type K-ras associated with a high EGFR GCN can predict sensitivity to cetuximab-based treatment.

Lie-specific involvement of dorsolateral prefrontal cortex in deception.

Lies are intentional distortions of event knowledge. No experimental data are available on manipulating lying processes. To address this issue, we stimulated the dorsolateral prefrontal cortex (DLPFC) using transcranial direct current stimulation (tDCS). Fifteen healthy volunteers were tested before and after tDCS (anodal, cathodal, and sham). Two types of truthful (truthful selected: TS; truthful unselected: TU) and deceptive (lie selected: LS; lie unselected: LU) responses were evaluated using a computer-controlled task. Reaction times (RTs) and accuracy were collected and used as dependent variables. In the baseline task, the RT was significantly longer for lie responses than for true responses ([mean +/- standard error] 1153.4 +/- 42.0 ms vs. 1039.6 +/- 36.6 ms; F(1,14) = 27.25, P = 0.00013). At baseline, RT for selected pictures was significantly shorter than RT for unselected pictures (1051.26 +/- 39.0 ms vs. 1141.76 +/- 41.1 ms; F(1,14) = 34.85, P = 0.00004). Whereas after cathodal and sham stimulation, lie responses remained unchanged (cathodal 5.26 +/- 2.7%; sham 5.66 +/- 3.6%), after anodal tDCS, RTs significantly increased but did so only for LS responses (16.86 +/- 5.0%; P = 0.002). These findings show that manipulation of brain function with DLPFC tDCS specifically influences experimental deception and that distinctive neural mechanisms underlie different types of lies.

Expression of estrogen receptor in hemangioma of the uterine cervix: reports of three cases and review of the literature.

The occurrence of hemangioma in the female genital tract, particularly in uterine cervix, is rare. The majority of them show asymptomatic behavior. Surgical excision remains curative in most of the cases. Conservative therapies such as sclerosing agents, cryotherapy, and CO(2) laser excision may be alternatively applied. We present three cases of hemangiomas of the cervix in asymptomatic women, diagnosed as cavernous hemangioma in two cases and capillary hemangioma in one. All tumors were immunoreactive for CD31, CD34, factor-VIII-related antigen. Focal expression of estrogen receptors was detected. No positivity was obtained with progesterone receptor antibodies. The presence of estrogen receptor in the endothelial cells of the hemangioma of the cervix suggests a direct role of this hormone in the hemangioma development. A possible target therapy is discussed.

Tumor cell proliferation and microsatellite alterations in human ameloblastoma.

Ameloblastoma is the most common odontogenic tumor. It can exhibit a variety of histological patterns, a great infiltrative potential and a high recurrence rate. Mutations in microsatellite sequences are a hallmark of neoplastic transformation but little is known about their role in ameloblastoma development. In this study DNA was extracted from laser-microdissected samples of 24 ameloblastomas and was analyzed for the status of 22 microsatellite loci. The occurrence and the pattern of microsatellite alterations, in form of loss or length variation, was evaluated and correlated with the Ki67 labeling index and with other clinicopathologic parameters. The prognostic significance of these alterations was also evaluated. High Ki67 expression was significantly associated with a shorter disease-free survival (p=0.003 by log-rank test). Alterations of at least one of the selected loci was observed in all (100%) the ameloblastomas analyzed with a mean of 4 altered microsatellites for each tumor. The microsatellites most frequently altered were D9S747 and D11S488 (42%). All the other loci analyzed were altered in less than 40% of cases and some of them (D3S1312, D3S1300, IFNA, D9S164, D13S176 and TP53) did not show alterations in any of the ameloblastomas analyzed. No relationship was observed between the occurrence of microsatellite alterations and other parameters, such as patients age and gender, tumor size, localization and histotype. The occurrence of microsatellite alterations was more frequent in tumors displaying a high Ki67 labeling index (p=0.03) and in a univariate analysis was predictor of an increased risk of disease recurrence (p=0.039 by log-rank test). These findings demonstrate that microsatellite alterations are frequent event in ameloblastomas. They also suggest that evaluation of tumor cells proliferative activity and microsatellite alterations may be helpful to stratify ameloblastomas prognostically and to predict the clinical behavior of these tumors.

The charm of structural neuroimaging in insanity evaluations: guidelines to avoid misinterpretation of the findings.

Despite the popularity of structural neuroimaging techniques in twenty-first-century research, its results have had limited translational impact in real-world settings, where inferences need to be made at the individual level. Structural neuroimaging methods are now introduced frequently to aid in assessing defendants for insanity in criminal forensic evaluations, with the aim of providing "convergence" of evidence on the mens rea of the defendant. This approach may provide pivotal support for judges' decisions. Although neuroimaging aims to reduce uncertainty and controversies in legal settings and to increase the objectivity of criminal rulings, the application of structural neuroimaging in forensic settings is hampered by cognitive biases in the evaluation of evidence that lead to misinterpretation of the imaging results. It is thus increasingly important to have clear guidelines on the correct ways to apply and interpret neuroimaging evidence. In the current paper, we review the literature concerning structural neuroimaging in court settings with the aim of identifying rules for its correct application and interpretation. These rules, which aim to decrease the risk of biases, focus on the importance of (i) descriptive diagnoses, (ii) anatomo-clinical correlation, (iii) brain plasticity and (iv) avoiding logical fallacies, such as reverse inference. In addition, through the analysis of real forensic cases, we describe errors frequently observed due to incorrect interpretations of imaging. Clear guidelines for both the correct circumstances for introducing neuroimaging and its eventual interpretation are defined.

Semantic relevance best predicts normal and abnormal name retrieval.

The relevance of a semantic feature measures its contribution to the "core" meaning of a concept. In a naming-to-description task, we investigated the predictive power of relevance in comparison with frequency, familiarity, typicality, and Age-of-Acquisition. In a group of Alzheimer patients with semantic disorder, relevance turned out to be the best predictor of name retrieval accuracy in a naming-to-description task. The same pattern of results was observed in normal controls. Relations between semantic relevance and the parameters of the concepts are discussed in order to highlight the mechanism of concept activation in a naming-to-description task.

The value of c-kit mutational analysis in a cytokeratin positive gastrointestinal stromal tumour.

The expression of cytokeratins in gastrointestinal stromal tumours (GISTs) is rare and may lead to diagnostic confusion when it occurs. This report describes a metastatic GIST that stained strongly for cytokeratins, CD117, and CD34 in a patient who was previously diagnosed with gastric epithelioid angiosarcoma. A review of both tumours showed the same histological and immunohistochemical profiles, and c-kit molecular analysis revealed an insertional mutation at codon 558 of exon 11 in both tumours. Thus, pathologists should be aware that GISTs can occasionally express cytokeratins, and that c-kit mutational investigations may have a key diagnostic role and may prevent diagnostic mistakes that could have important clinical implications.

Deficits in the control of the attentional focus in chronic schizophrenics.

The ability to control the size of the attentional focus and thus to modulate processing efficiency was investigated using simple reaction times in central vision in 17 chronic schizophrenic patients and 17 normal control subjects. The size of the attentional focus was manipulated by varying the size of a central box (i.e., a pre-cue), where the imperative stimulus appeared. In accordance with previous studies, in normal controls reaction time increased with box size. In contrast, in schizophrenic patients reaction time did not depend on box size. That is, schizophrenic patients did not show the inverse relation between size of the box and speed of processing, which is observed in normal controls. These results suggest that a deficit in controlling the size of the attentional focus is a basic impairment in chronic schizophrenia. It was also found that schizophrenics are more susceptible than controls to paracontrast.

A letter-by-letter reader who could not read nonwords.

Letter-by-letter reading is a neuropsychological syndrome characterized by oral reading which seems to be mediated by explicit naming of constituent letters of the printed string. Thus reading time rises abnormally as a function of the length of the items to-be-read. This syndrome is generally interpreted as indicating a disconnection within the normal reading system prior to the activation of the visual and phonological lexical access routes. The patient retains a subsidiary strategy of spelling words by naming their constituent letters and uses this strategy for planning their pronunciation. If this interpretation is correct then reading aloud in letter-by-letter reading should not be affected by the features of the letter string which are stored lexically as the functional disconnection is postulated to occur prior to this stage. In this paper we report the case of a letter-by-letter reader who shows some signs which are puzzling in terms of current interpretations of the syndrome. They can be summarized as follows: (1) The patient reads words better than he reads nonwords; (2) Concrete words are processed more holistically while abstract words are processed more letter-by-letter; (3) Lexical decisions can be made far more rapidly than words can be read aloud. These three signs are very difficult to account for if reading is accomplished solely through a non-lexical reversed spelling strategy. Our experimental investigations of this patient are reported and alternative models assuming strategic control over the reading mechanism are discussed.

Thiazorifamycins. III. Biosynthesis of rifamycins P, Q and verde, novel metabolites from a mutant of Nocardia mediterranea.

The thiazorifamycins are derived from rifamycin S and cysteine; rifamycins P and Verde are formed by chemical reactions, while rifamycin Q synthesis involves obligatory enzymatic assistance. All antibiotics come from a common six-member precursor lacking C-1 of cysteine; the thiazin-2-one ring of rifamycin Verde retains both C-2 and C-3 of cysteine, while the thiazole ring of rifamycins P and Q retains only C-2, C-3 becoming exocyclic in the ring-contraction C-3 is present in rifamycin Q but not in P.

Progressive visual agnosia with posterior cortical atrophy.

A patient of posterior cortical atrophy characterized by early signs of progressive visual agnosia documented by repeated neuropsychological tests, is reported. SPECT and MRI findings showed left unilateral parieto-occipital involvement in the earlier stage. A PET study executed eight months later showed bilateral parieto-occipital hypometabolism, but predominantly in the left hemisphere. This suggests that the degeneration may have developed asymmetrically, progressing from left unilateral to bilateral.

How to avoid the fallacies of cognitive subtraction in brain imaging.

Functional neuroanatomy of cognitive processes is generally derived by subtraction of a control task from an experimental task. We show that this method is logically untenable and propose to replace it with an adaptation of the specific-effect method and of the additive-factor method. The basic flaw that undermines the subtractive method is the comparison between different tasks. We argue that the specific-effect method should be used when investigating activations produced by different levels of a qualitative variable, whereas the additive-factor method should be used for quantitative variables. The use of these methods allows one to distinguish between parallel and serial stages of processing and between local and distributed processing.