Detection and Clearance of Type-Specific and Phylogenetically Related Genital Human Papillomavirus Infections in Young Women in New Heterosexual Relationships.

BACKGROUND: Understanding the natural history of human papillomavirus (HPV) infections is essential to cervical cancer prevention planning. We estimated HPV type-specific infection detection and clearance in young women. METHODS: The HPV Infection and Transmission among Couples through Heterosexual activity (HITCH) study is a prospective cohort of 502 college-age women who recently initiated a heterosexual relationship. We tested vaginal samples collected at 6 clinical visits over 24 months for 36 HPV types. Using rates and Kaplan-Meier analysis, we estimated time-to-event statistics with 95% confidence intervals (CIs) for detection of incident infections and clearance of incident and present-at-baseline infections (separately). We conducted analyses at the woman- and HPV-levels, with HPV types grouped by phylogenetic relatedness. RESULTS: By 24 months, we detected incident infections in 40.4% (CI, 33.4%-48.4%) of women. Incident subgenus 1 (43.4; CI, 33.6-56.4), 2 (47.1; CI, 39.9-55.5), and 3 (46.6; CI, 37.7-57.7) infections cleared at similar rates per 1000 infection-months. We observed similar homogeny in HPV-level clearance rates among present-at-baseline infections. CONCLUSIONS: Our analyses provide type-specific infection natural history estimates for cervical cancer prevention planning. HPV-level analyses did not clearly indicate that high oncogenic risk subgenus 2 infections persist longer than their low oncogenic risk subgenera 1 and 3 counterparts.

Epidemiology of genital human papillomavirus infections in sequential male sex partners of young females.

OBJECTIVES: Couple-based studies have considered human papillomavirus (HPV) transmission between current heterosexual partners (male↔female). Using data from young women and their sequential male partners, we analysed HPV transmission from upstream sexual partnerships (male 1↔female) to downstream sex partners (→male 2). METHODS: Among 502 females enrolled in the HPV Infection and Transmission among Couples through Heterosexual activity study (2005-2011, Montréal, Canada), 42 brought one male sex partner at baseline (male 1) and another during follow-up (male 2). Female genital samples, collected at six visits over 24 months, and male genital samples, collected at two visits over 4 months, were tested for 36 HPV types (n = 1512 detectable infections). We calculated observed/expected ratios with 95% CIs for type-specific HPV concordance between males 1 and 2. Using mixed-effects regression, we estimated ORs with 95% CIs for male 2 testing positive for the same HPV type as male 1. RESULTS: Detection of the same HPV type in males 1 and 2 occurred 2.6 (CI 1.9-3.5) times more often than chance (29 instances observed vs. 10.95 instances expected). The OR for male 2 positivity was 4.2 (CI 2.5-7.0). Adjusting for the number of times the linking female tested positive for the same HPV type attenuated the relationship between male 1 and 2 positivity, suggesting mediation. CONCLUSIONS: High type-specific HPV concordance between males 1 and 2 confirms HPV's transmissibility in chains of sequential sexual partnerships. HPV positivity in an upstream partnership predicted positivity in a downstream male when the linking female partner was persistently positive.

Detection and clearance of type-specific and phylogenetically related genital human papillomavirus infections in young women in new heterosexual relationships.

Background: Understanding the natural history of human papillomavirus (HPV) infections is essential to effective cervical cancer prevention planning. We examined these outcomes in-depth among young women. Methods: The HPV Infection and Transmission among Couples through Heterosexual Activity (HITCH) study is a prospective cohort of 501 college-age women who recently initiated a heterosexual relationship. We tested vaginal samples collected at six clinical visits over 24 months for 36 HPV types. Using rates and Kaplan-Meier analysis, we estimated time-to-event statistics with 95% confidence intervals (CIs) for detection of incident infections and liberal clearance of incident and present-at-baseline infections (separately). We conducted analyses at the woman- and HPV-levels, with HPV types grouped by phylogenetic relatedness. Results: By 24 months, we detected incident infections in 40.4%, CI:33.4-48.4 of women. Incident subgenus 1 (43.4, CI:33.6-56.4), 2 (47.1, CI:39.9-55.5) and 3 (46.6, CI:37.7-57.7) infections cleared at similar rates per 1000 infection-months. We observed similar homogeny in HPV-level clearance rates among present-at-baseline infections. Conclusions: Our woman-level analyses of infection detection and clearance agreed with similar studies. However, our HPV-level analyses did not clearly indicate that high oncogenic risk subgenus 2 infections take longer to clear than their low oncogenic risk and commensal subgenera 1 and 3 counterparts.

Author Correction: Selective, high-contrast detection of syngeneic glioblastoma in vivo.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Selective, high-contrast detection of syngeneic glioblastoma in vivo.

Glioblastoma is a highly malignant, largely therapy-resistant brain tumour. Deep infiltration of brain tissue by neoplastic cells represents the key problem of diffuse glioma. Much current research focuses on the molecular makeup of the visible tumour mass rather than the cellular interactions in the surrounding brain tissue infiltrated by the invasive glioma cells that cause the tumour's ultimately lethal outcome. Diagnostic neuroimaging that enables the direct in vivo observation of the tumour infiltration zone and the local host tissue responses at a preclinical stage are important for the development of more effective glioma treatments. Here, we report an animal model that allows high-contrast imaging of wild-type glioma cells by positron emission tomography (PET) using [18 F]PBR111, a selective radioligand for the mitochondrial 18 kDa Translocator Protein (TSPO), in the Tspo-/- mouse strain (C57BL/6-Tspotm1GuMu(GuwiyangWurra)). The high selectivity of [18 F]PBR111 for the TSPO combined with the exclusive expression of TSPO in glioma cells infiltrating into null-background host tissue free of any TSPO expression, makes it possible, for the first time, to unequivocally and with uniquely high biological contrast identify peri-tumoral glioma cell invasion at preclinical stages in vivo. Comparison of the in vivo imaging signal from wild-type glioma cells in a null background with the signal in a wild-type host tissue, where the tumour induces the expected TSPO expression in the host's glial cells, illustrates the substantial extent of the peritumoral host response to the growing tumour. The syngeneic tumour (TSPO+/+) in null background (TSPO-/-) model is thus well suited to study the interaction of the tumour front with the peri-tumoral tissue, and the experimental evaluation of new therapeutic approaches targeting the invasive behaviour of glioblastoma.

Translocator protein localises to CD11b+ macrophages in atherosclerosis.

BACKGROUND AND AIMS: Atherosclerosis is characterized by lipid deposition, monocyte infiltration and foam cell formation in the artery wall. Translocator protein (TSPO) is abundantly expressed in lipid rich tissues. Recently, TSPO has been identified as a potential diagnostic tool in cardiovascular disease. The purpose of this study was to determine if the TSPO ligand, 18F-PBR111, can identify early atherosclerotic lesions and if TSPO expression can be used to identify distinct macrophage populations during lesion progression. METHODS: ApoE-/- mice were maintained on a high-fat diet for 3 or 12 weeks. C57BL/6J mice maintained on chow diet served as controls. Mice were administered 18F-PBR111 intravenously and PET/CT imaged. After euthanasia, aortas were isolated, fixed and optically cleared. Cleared aortas were immunostained with DAPI, and fluorescently labelled with antibodies to TSPO, the tissue resident macrophage marker F4/80 and the monocyte-derived macrophage marker CD11b. TSPO expression and the macrophage markers were visualised in fatty streaks and established plaques by light sheet microscopy. RESULTS: While tissue resident F4/80 + macrophages were evident in the arteries of animals without atherosclerosis, no CD11b + macrophages were observed in these animals. In contrast, established plaques had high CD11b and low F4/80 expression. A ∼3-fold increase in the uptake of 18F-PBR111 was observed in the aortas of atherosclerotic mice relative to controls. CONCLUSIONS: Imaging of TSPO expression is a new approach for studying atherosclerotic lesion progression and inflammatory cell infiltration. The TSPO ligand, 18F-PBR111, is a potential clinical diagnostic tool for the detection and quantification of atherosclerotic lesion progression in humans.

In vivo [64Cu]CuCl2 PET imaging reveals activity of Dextran-Catechin on tumor copper homeostasis.

Given the strong clinical evidence that copper levels are significantly elevated in a wide spectrum of tumors, copper homeostasis is considered as an emerging target for anticancer drug design. Monitoring copper levels in vivo is therefore of paramount importance when assessing the efficacy of copper-targeting drugs. Herein, we investigated the activity of the copper-targeting compound Dextran-Catechin by developing a [64Cu]CuCl2 PET imaging protocol to monitor its effect on copper homeostasis in tumors. Methods: Protein expression of copper transporter 1 (CTR1) in tissue microarrays representing 90 neuroblastoma patient tumors was assessed by immunohistochemistry. Western blotting analysis was used to study the effect of Dextran-Catechin on the expression of CTR1 in neuroblastoma cell lines and in tumors. A preclinical human neuroblastoma xenograft model was used to study anticancer activity of Dextran-Catechin in vivo and its effect on tumor copper homeostasis. PET imaging with [64Cu]CuCl2 was performed in such preclinical neuroblastoma model to monitor alteration of copper levels in tumors during treatment. Results: CTR1 protein was found to be highly expressed in patient neuroblastoma tumors by immunohistochemistry. Treatment of neuroblastoma cell lines with Dextran-Catechin resulted in decreased levels of glutathione and in downregulation of CTR1 expression, which caused a significant decrease of intracellular copper. No changes in CTR1 expression was observed in normal human astrocytes after Dextran-Catechin treatment. In vivo studies and PET imaging analysis using the neuroblastoma preclinical model revealed elevated [64Cu]CuCl2 retention in the tumor mass. Following treatment with Dextran-Catechin, there was a significant reduction in radioactive uptake, as well as reduced tumor growth. Ex vivo analysis of tumors collected from Dextran-Catechin treated mice confirmed the reduced levels of CTR1. Interestingly, copper levels in blood were not affected by treatment, demonstrating potential tumor specificity of Dextran-Catechin activity. Conclusion: Dextran-Catechin mediates its activity by lowering CTR1 and intracellular copper levels in tumors. This finding further reveals a potential therapeutic strategy for targeting copper-dependent cancers and presents a novel PET imaging method to assess patient response to copper-targeting anticancer treatments.

Robotic-assisted Laparoscopic Pyeloplasty: Analysis of Symptomatic Patients With Equivocal Renal Scans.

OBJECTIVES: To review the objective and subjective success rates of robotic-assisted laparoscopic pyeloplasty in symptomatic patients with radiographic findings suggestive of uretero-pelvic junction obstruction (UPJO), but equivocal renal scans (diuretic T1/2 <20 minutes). METHODS: We reviewed 77 patients with symptomatic UPJO, who underwent robotic-assisted laparoscopic pyeloplasty between August 2006 and March 2013. We grouped patients by renal scan findings into 1 of 2 groups, obstructed (diuretic T1/2 ≥20 minutes) or equivocal (diuretic T1/2 <20 minutes). All patients were symptomatic and had radiographic findings suggestive of UPJO (eg hydronephrosis). RESULTS: Mean age was 40.7 years (range 17-80) with 70% female. UPJO occurred 44% left and 56% right, with 92% presenting with flank pain. Of 77 patients, 45 had obstruction on renal scan, with 41 (91%) having resolution of obstruction postoperatively and 44 of 45 (98%) having complete resolution of their initial symptoms. Thirty-two patients had equivocal findings with mean diuretic T1/2 of 12.6 minutes (range: 5.5-19.26) on renal scan. In this latter group, patients had significantly less of a decrease in their diuretic T1/2 postoperatively (4 vs 64 minutes, P = .018) and reported less pain resolution (53% vs 98%, P ≤.001) than group 1. CONCLUSION: Many studies have demonstrated excellent success of pyeloplasty, with most series including patients meeting strict diagnostic criteria for obstruction. Our study examines outcomes in patients with clinically symptomatic UPJO and equivocal diuretic renography. In our cohort, equivocal patients were significantly less likely to have subjective resolution of symptoms than patients in the obstructed group.

Synthesis and biological characterisation of 18F-SIG343 and 18F-SIG353, novel and high selectivity σ2 radiotracers, for tumour imaging properties.

BACKGROUND: Sigma2 (σ2) receptors are highly expressed in cancer cell lines and in tumours. Two novel selective 18F-phthalimido σ2 ligands, 18F-SIG343 and 18F-SIG353, were prepared and characterised for their potential tumour imaging properties. METHODS: Preparation of 18F-SIG343 and 18F-SIG353 was achieved via nucleophilic substitution of their respective nitro precursors. In vitro studies including radioreceptor binding assays in the rat brain membrane and cell uptake studies in the A375 cell line were performed. In vivo studies were carried out in mice bearing A375 tumours including positron emission tomography (PET) imaging, biodistribution, blocking and metabolite studies. RESULTS: In vitro studies showed that SIG343 and SIG353 displayed excellent affinity and selectivity for σ2 receptors (Ki(σ2) = 8 and 3 nM, σ2:σ1 = 200- and 110-fold, respectively). The σ2 selectivity of 18F-SIG343 was further confirmed by blocking studies in A375 cells, however, not noted for 18F-SIG353. Biodistribution studies showed that both radiotracers had similar characteristics including moderately high tumour uptake (4%ID/g to 5%ID/g); low bone uptake (3%ID/g to 4%ID/g); and high tumour-to-muscle uptake ratios (four- to sevenfold) up to 120 min. Although radiotracer uptake in organs known to express σ receptors was significantly blocked by pre-injection of competing σ ligands, the blocking effect was not observed in the tumour. PET imaging studies indicated major radioactive localisation in the chest cavity for both ligands, with approximately 1%ID/g uptake in the tumour at 120 min. Metabolite studies showed that the original radiotracers remained unchanged 65% to 80% in the tumour up to 120 min. CONCLUSIONS: The lead ligands showed promising in vitro and in vivo characteristics. However, PET imaging indicated low tumour-to-background ratios. Furthermore, we were unable to demonstrate that uptake in the A375 tumour was σ2-specific. 18F-SIG343 and 18F-SIG343 do not display ideal properties for imaging the σ2 receptor in the A375 tumour model. However, since the radiotracers show promising in vitro and in vivo characteristics, longer scans using appropriate half-life isotopes and alternative tumour models will be carried out in future studies to fully validate the imaging characteristics of these radiotracers.

Successful treatment of esophageal metastasis from hepatocellular carcinoma using the da Vinci robotic surgical system.

A 59-year-old man with metastatic an esophageal tumor from hepatocellular carcinoma (HCC) presented with progressive dysphagia. He had undergone liver transplantation for HCC three and a half years prevously. At presentation, his radiological and endoscopic examinations suggested a submucosal tumor in the lower esophagus, causing a luminal stricture. We performed complete resection of the esophageal metastases and esophagogastrostomy reconstruction using the da Vinci robotic system. Recovery was uneventful and he was been doing well 2 mo after surgery. α-fetoprotein level decreased from 510 ng/mL to 30 ng/mL postoperatively. During the follow-up period, he developed a recurrent esophageal stricture at the anastomosis site and this was successfully treated by endoscopic esophageal dilatation.

Proximal tibial opening wedge osteotomy as the initial treatment for chronic posterolateral corner deficiency in the varus knee: a prospective clinical study.

BACKGROUND: Nonoperative treatment of posterolateral knee injuries tends to yield poor results. In patients with chronic posterolateral knee injuries, failure to correct genu varus alignment will often result in failure of the posterolateral knee repair or reconstruction. PURPOSE: To prospectively assess the functional outcomes of patients with combined grade 3 posterolateral instability and genu varus alignment initially treated with a proximal tibial opening wedge osteotomy. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: Twenty-one patients with combined chronic posterolateral corner deficiency and genu varus alignment were initially treated with a proximal tibial opening wedge osteotomy and observed prospectively. Second-stage ligamentous reconstruction was performed in patients with continued clinical and functional instability after the osteotomies had healed and they had undergone at least 3 months of rehabilitation. RESULTS: At a mean follow-up of 37 months, 8 of 21 patients (38%) had sufficient improvement in knee function that a subsequent posterolateral corner reconstruction was not necessary. There was a significant difference in coronal alignment between the preoperative and postoperative mechanical axis action point. There were no significant differences in the preoperative and postoperative posterior tibial slope. Thirteen patients underwent a second-stage ligament reconstruction at an average of 13.8 months after the initial osteotomy procedure. Final postoperative Cincinnati Knee Rating System scores were significantly lower for those patients who required a subsequent posterolateral corner reconstruction than for those patients who did not have a reconstruction. The P value for the preoperative differences between groups was not significant (P = .11). Seven of 9 patients with high-velocity knee injuries required a second-stage reconstruction. Ten of 14 patients (71%) with multiligament knee injuries required a posterolateral corner reconstruction. In contrast, 4 of 6 patients (67%) with an isolated posterolateral corner injury did not require a second-stage ligament reconstruction. CONCLUSION: Proximal tibial opening wedge osteotomy can be an effective first method of treatment for patients with chronic combined posterolateral knee injuries and genu varus alignment. Patients with low-velocity knee injuries and isolated chronic posterolateral knee injuries may not require a second-stage soft tissue ligament reconstruction after healing the osteotomy and undergoing a program of rehabilitation.