Detection of high-grade cervical neoplasia using extended genotyping: Performance data from the longitudinal phase of the Onclarity trial.

OBJECTIVES: The Onclarity cervical cancer screening trial was designed to establish the clinical validity of the Onclarity HPV assay for extended genotyping (xGT) during detection of high-grade cervical neoplasia grades 2 or 3 (≥CIN2 or ≥CIN3). Here, three-year follow up data is presented to evaluate the overall efficacy of these screening strategies, compared to the baseline data. METHODS: At baseline 29,513 women, ≥25 years, had evaluable cytology and valid high-risk HPV results. Women with atypical squamous cells-undetermined significance or worse cytology or a positive HPV test were referred for colposcopy/biopsy. Participants that did not reach the study end point (treatment for ≥CIN2) continued into the longitudinal phase that included the same protocol as baseline. RESULTS: The three-year cumulative incident risk (CIR) for ≥CIN3 in HPV-negative women was 0.15% [95%CI: 0.06, 0.26] and for HPV- and cytology-negative women was 0.12% [95% CI: 0.03,0.23]. HPV16 carried the highest baseline and three-year ≥CIN3 CIR, followed by HPV31 and HPV18. At least one year of genotype-specific persistence increased ≥CIN3 risk for xGT results compared to genotype non-persistence, HPV clearance, or new infection over the same time period. Risk-based screening with immediate colposcopy for HPV16/18/31 and further xGT triage resulted in better ≥CIN3 sensitivity (79.2% versus 72.3%; relative difference of 6.9 [95%CI: 3.3, 10.4]) and a lower colposcopy/≥CIN3 ratio (9.2 versus 11.2; relative difference of -1.9 [95%CI: -2.6, -1.3]) when compared to primary HPV16/18-based screening. CONCLUSIONS: An HPV-negative result offers the same assurance of no disease over three years of follow up as that offered by a negative co-testing result. xGT facilitates risk-based screening and persistence tracking and can help optimize disease detection during screening without excessive colposcopic procedures.

Dermatofibrosarcoma Protuberans in Children.

OPINION STATEMENT: Paediatric dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue malignant tumour which displays aggressive local behaviour and has low metastatic potential. The diagnosis is often delayed as DFSP is usually mistaken for other skin conditions, particularly in the early stages of disease. DFSP tends to follow an indolent course after the initial presentation with what is often described as a "rubbery lump". As the disease progresses, the lump tends to enlarge, change colour, and exhibit a more nodular consistency. In rare cases, DFSP can present as an ulcerated exophytic lesion or a depressed area of skin, making diagnosis even more challenging. A high index of suspicion is warranted for early diagnosis, and referral to a specialist unit with expertise in both oncologic resection and reconstruction. DFSP tumours arise from the dermis and grow with finger-like projections. Therefore, in cosmetically sensitive or functionally important locations, an excision and analysis technique that assesses all excision margins is the gold standard of care. Slow Mohs technique performed with en bloc excision is a well-tolerated option for oncologic resection of the tumour. Mohs technique can also be considered but can be challenging in children for reasons explained below. As an alternative, depending on the anatomical location, tumours can be excised with a wide local excision. While an excision technique that incorporates the deep fascia with a 3-cm peripheral margin is acceptable in adults, planning of the excision margin in children should involve consideration of preoperative imaging with MRI, site of the tumour, age, and physical built of the child. Patients should be offered all treatment options considering the local outcomes, available expertise, and cost. A multidisciplinary approach and good communication between team members is crucial. Close collaboration with a pathologist who is familiar with sectioning technique that allows margin control is of paramount importance. Soft tissue reconstruction should be performed immediately after oncologic clearance, although a staged approach may be required. Adjuvant radiotherapy should be avoided in children due to the long-term risk of secondary malignancies and potential for growth disruption.

Liposarcoma subtype recurrence and survival: A UK regional cohort study.

BACKGROUND: Clinical outcome data in the United Kingdom, Europe, and the United States have yet to facilitate appropriately specific surveillance for liposarcoma histological subtypes, despite being one of the most common soft tissue sarcomas. Therefore, this study aims to demonstrate histologic-specific differences in liposarcoma recurrence, disease progression, and survival and discuss the implications. METHODS AND FINDINGS: This cohort study involves patients from a regional sarcoma service in the UK who have had a primary surgical excision of liposarcoma between October 2002 and September 2019. The median follow-up is five years. Confirmed histopathological diagnoses of liposarcoma (n = 193) are organised according to the World Health Organisation recognised subtypes: atypical lipomatous tumours (ALT), myxoid, pleomorphic, and dedifferentiated liposarcomas. In addition, retroperitoneal variants (n = 34) are included to illustrate the broader spectrum of phenotypes. The primary outcomes were local recurrence, distant disease progression, and disease-specific death, and compared using Kaplan-Meier analyses and tumour variables using Cox proportional hazard analyses. All three primary outcomes significantly differed (P < 0.0001, n = 193). There were no metastases or disease-specific death in patients with ALT (n = 92) and no metastases of their retroperitoneal counterparts (n = 17). Amongst the metastasising cases of rarer subtypes, there were pulmonary spread of pleomorphic (8/9, n = 20), dedifferentiated (4/5, n = 18), and myxoid (2/3, n = 29) liposarcomas. CONCLUSION: An absence of metastases of ALT should be considered alongside global evidence. Surveillance protocols could better differentiate between these subtypes and, in doing so, save patients a considerable amount of irradiation, time, fear, and anxiety.

Clinical Utility of Reflex Testing with Cancer Biomarkers to Improve Diagnostic Accuracy of Primary Human Papillomavirus Screening.

BACKGROUND: Human papillomavirus (HPV) testing is the cornerstone of cervical cancer screening, with outstanding sensitivity but only moderate specificity. We evaluated whether reflex testing for cancer biomarkers improves the sensitivity/specificity balance of screening. METHODS: Cervical samples from women in Cape Town, South Africa, ages 30-65 years, were collected and tested with Xpert HPV and with real-time PCR to detect mRNA for cyclin-dependent kinase inhibitor 2A (CDKN2A), topoisomerase 2 alpha (TOP2A), and Ki67 (MKi67). Women with histologically confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+; 85 women without and 166 with HIV) and women with no cervical disease (331 without and 257 with HIV) were included. RESULTS: When used as reflex tests after a positive HPV result, biomarkers discriminated well between women with and without CIN2+. The inclusion of both CDKN2A and MKi67 had the best performance, with area under the curve (AUC) of 0.9171 and 0.8734 in women without and with HIV, respectively. Although excellent, these performance parameters did not improve on an approach utilizing only HPV testing with more stringent cycle threshold cutoffs and HPV genotype selection, which achieved AUC of 0.9059 and 0.8705 in women without and with HIV, respectively. CONCLUSIONS: Biomarkers can be used as triage after positive HPV results but do not outperform an approach utilizing higher viral load cutoffs on selected high-risk genotypes. IMPACT: A screening approach using HPV testing alone can be more easily implemented at the point of care.

Clinical validation of p16/Ki-67 dual-stained cytology triage of HPV-positive women: Results from the IMPACT trial.

Triage strategies are needed for primary human papillomavirus (HPV)-based cervical cancer screening to identify women requiring colposcopy/biopsy. We assessed the performance of p16/Ki-67 dual-stained (DS) immunocytochemistry to triage HPV-positive women and compared it to cytology, with or without HPV16/18 genotyping. A prospective observational screening study enrolled 35 263 women aged 25 to 65 years at 32 U.S. sites. Cervical samples had HPV and cytology testing, with colposcopy/biopsy for women with positive tests. Women without cervical intraepithelial neoplasia Grade 2 or worse (≥CIN2) at baseline (n = 3876) were retested after 1 year. In all, 4927 HPV-positive women with valid DS results were included in this analysis. DS sensitivity for ≥CIN2 and ≥CIN3 at baseline was 91.2% (95% confidence interval [CI]: 86.8%-94.2%) and 91.9% (95% CI: 86.1%-95.4%), respectively, in HPV16/18-positive women and 83.0% (95% CI: 78.4%-86.8%) and 86.0% (95% CI: 77.5%-91.6%) in women with 12 "other" genotypes. Using DS alone to triage HPV-positive women showed significantly higher sensitivity and specificity than HPV16/18 genotyping with cytology triage of 12 "other" genotypes, and substantially higher sensitivity but lower specificity than using cytology alone. The risk of ≥CIN2 was significantly lower in HPV-positive, DS-negative women (3.6%; 95% CI: 2.9%-4.4%), compared to triage-negative women using HPV16/18 genotyping with cytology for 12 "other" genotypes (7.4%; 95% CI: 6.4%-8.5%; P < .0001) or cytology alone (7.5%; 95% CI: 6.7%-8.4%; P < .0001). DS showed better risk stratification than cytology-based strategies and provided high reassurance against pre-cancers both at baseline and at 1-year follow-up, irrespective of the HPV genotype. DS allows for the safe triage of primary screening HPV-positive women.

The CERTAIN Study Results: Adjunctive p16 Immunohistochemistry Use in Cervical Biopsies According to LAST Criteria.

The Lower Anogenital Squamous Terminology (LAST) Project recommends the use of p16 immunohistochemistry as an adjunct to morphologic assessment of cervical biopsies according to a specific set of criteria. We analyzed the effect of adjunctive p16 according to LAST criteria in a US-based diagnostic utility study involving 70 surgical pathologists providing a total of 38,500 reads on cervical biopsies. Compared with the results obtained using hematoxylin and eosin-stained slides only, including p16-stained slides per LAST criteria increased sensitivity and specificity for diagnosing histologic high-grade squamous intraepithelial lesions across all cases by 8.1% (95% confidence interval [95% CI], 6.5-9.7; P<0.0001) and 3.5% (95% CI, 2.8-4.2; P<0.0001), respectively, using expert consensus diagnoses on hematoxylin and eosin+p16 as reference. Within the subset of cases classified by the pathologists as fulfilling the LAST criteria, adding p16 significantly increased both sensitivity (+11.8%; 95% CI, 9.5-14.0; P<0.0001) and specificity (+9.7%; 95% CI, 7.8-11.5; P<0.0001). However, a comparable improvement in sensitivity (+11.0%; 95% CI, 7.8-14.1; P<0.0001) was found when p16 was used in cases for which p16 staining was not ordered per LAST by the pathologists, whereas specificity decreased by -0.8% (95% CI, -1.1 to -0.5; P<0.0001). The study demonstrates a clinically and statistically significant increase in sensitivity and specificity for high-grade squamous intraepithelial lesion when p16 is used according to LAST criteria. Expanding the use of p16 into non-LAST cases would lead to a comparable improvement in sensitivity within this subgroup of biopsies, at the cost of a minimal, but statistically significant difference in specificity.

Orthoplastic management of open tibial fractures in children : a consecutive five-year series from a paediatric major trauma centre.

AIMS: Open tibial fractures are limb-threatening injuries. While limb loss is rare in children, deep infection and nonunion rates of up to 15% and 8% are reported, respectively. We manage these injuries in a similar manner to those in adults, with a combined orthoplastic approach, often involving the use of vascularised free flaps. We report the orthopaedic and plastic surgical outcomes of a consecutive series of patients over a five-year period, which includes the largest cohort of free flaps for trauma in children to date. METHODS: Data were extracted from medical records and databases for patients with an open tibial fracture aged < 16 years who presented between 1 May 2014 and 30 April 2019. Patients who were transferred from elsewhere were excluded, yielding 44 open fractures in 43 patients, with a minimum follow-up of one year. Management was reviewed from the time of injury to discharge. Primary outcome measures were the rate of deep infection, time to union, and the Modified Enneking score. RESULTS: The mean age of the patients was 9.9 years (2.8 to 15.8), and 28 were male (64%). A total of 30 fractures (68%) involved a motor vehicle collision, and 34 (77%) were classified as Gustilo Anderson (GA) grade 3B. There were 17 (50%) GA grade 3B fractures, which were treated with a definitive hexapod fixator, and 33 fractures (75%) were treated with a free flap, of which 30 (91%) were scapular/parascapular or anterolateral thigh (ALT) flaps. All fractures united at a median of 12.3 weeks (interquartile range (IQR) 9.6 to 18.1), with increasing age being significantly associated with a longer time to union (p = 0.005). There were no deep infections, one superficial wound infection, and the use of 20 fixators (20%) was associated with a pin site infection. The median Enneking score was 90% (IQR 87.5% to 95%). Three patients had a bony complication requiring further surgery. There were no flap failures, and eight patients underwent further plastic surgery. CONCLUSION: The timely and comprehensive orthoplastic care of open tibial fractures in this series of patiemts aged < 16 years resulted in 100% union and 0% deep infection, with excellent patient-reported functional outcomes. Cite this article: Bone Joint J 2021;103-B(6):1160-1167.

The IMproving Primary Screening And Colposcopy Triage trial: human papillomavirus, cervical cytology, and histopathologic results from the baseline and 1-year follow-up phase.

BACKGROUND: An increase in human papillomavirus test volumes is expected in the near future because human papillomavirus-based screening protocols are expected to become more widely adopted. OBJECTIVE: The IMproving Primary Screening And Colposcopy Triage trial, a prospective, multicenter, US-based cervical cancer screening trial, was conducted to obtain US Food and Drug Administration approvals for the new, high-throughput cobas human papillomavirus (cobas HPV) test for use on the cobas 6800/8800 Systems (cobas HPV) for detecting cervical precancerous and cancerous cells (cervical intraepithelial neoplasia of grade 2 or worse and grade 3 or worse). Here, the baseline demographics, human papillomavirus test results, cervical cytology, and histopathologic results are presented. In addition, the baseline and 1-year risks of cervical intraepithelial neoplasia grade 2 or worse and grade 3 or worse associated with the human papillomavirus results are reported. STUDY DESIGN: In total, 35,263 women aged between 25 and 65 years undergoing routine screening were enrolled; liquid-based cytology and 2 polymerase chain reaction-based tests for high-risk human papillomavirus were performed. Women with abnormal Papanicolaou cytology, women positive for high-risk human papillomavirus by either of the 2 human papillomavirus tests, and a random subset of women negative according to the Papanicolaou cytology and the 2 human papillomavirus tests were referred for a colposcopy and cervical biopsy. Women who did not meet the study endpoint were eligible for the 1-year follow-up study phase. Verification bias-adjusted cervical disease prevalence and risks and 95% confidence intervals were computed. RESULTS: The prevalence of atypical squamous cells of undetermined significance and worse than atypical squamous cells of undetermined significance cytology were 6.5% and 3.2%, respectively. Prevalence of high-risk human papillomavirus, human papillomavirus 16, and human papillomavirus 18 based on the new cobas HPV test were 15.1%, 3.1%, and 1.4%, respectively. Both cytologic abnormalities and human papillomavirus positivity declined with increasing age. Among women who had a colposcopy and biopsy, the prevalence of cervical intraepithelial neoplasia grade 2 or worse and grade 3 or worse were 8.8% and 3.6%, respectively. The baseline and 1-year cumulative risks for cervical intraepithelial neoplasia grade 3 or worse were 13.6% and 16.9%, respectively, among women who tested positive for human papillomavirus 16. Women who tested negative for human papillomavirus had the lowest 1-year cumulative risk for cervical intraepithelial neoplasia grade 3 or worse (0.06%). CONCLUSION: The contemporary, age-specific prevalence of human papillomaviruses (including human papillomavirus 16 and 18), cytologic abnormalities, and cervical intraepithelial neoplasia in a large, US-based cervical cancer screening population provides benchmarks for healthcare policies, screening programs, and for laboratories and clinicians.

Performance of Xpert HPV on Self-collected Vaginal Samples for Cervical Cancer Screening Among Women in South Africa.

OBJECTIVES: Self-sampling may increase access to cervical cancer screening in low-resource settings. Using Xpert HPV, we compared test performance of self- and clinician-collected samples in HIV-positive and HIV-negative women in South Africa. MATERIALS AND METHODS: Three hundred thirty HIV-positive and 375 HIV-negative women in the screening group and 202 HIV-negative and 200 HIV-positive women in the referral group, aged 30-65 years, participated in the study. All women self-collected a vaginal sample, and then, a cervical sample was collected by a clinician (both tested using Xpert HPV), followed by colposcopic examination and collection of histologic specimens. RESULTS: There was good agreement between self- and clinician-collected samples for detection of any high-risk human papillomavirus (HPV, κ = 0.72 [95% CI = 0.669-0.771]). Prevalence of HPV and sensitivity of the test to detect cervical intraepithelial neoplasia 2+ was similar in self- and clinician-collected samples. Specificity was lower in self-collected than in clinician-collected samples in both HIV-negative (self: 77.5% [95% CI = 72.8-81.8] vs clinician: 86.9% [95% CI = 82.9-90.2]) and HIV-positive (self: 44.0% [95% CI = 38.0-50.1] vs clinician: 59.7% [95% CI = 53.6-65.6]) women. Restricting the definition of screen-positive to 3 of 5 channels on HPV Xpert improved specificity in both HIV-negative (self: 83.2% [95% CI = 78.8-87.0] vs clinician: 89.7% [95% CI = 86.1-92.7]) and HIV-positive (self: 54.2% [95% CI = 48.1-60.2] vs clinician: 67.4% [95% CI = 61.5-72.9]) women. CONCLUSIONS: The self-collected sample had good agreement with the clinician-collected sample for the detection of HPV, and restricting the HPV types may improve the specificity in HIV-positive women.

Analysis of Ugandan cervical carcinomas identifies human papillomavirus clade-specific epigenome and transcriptome landscapes.

Cervical cancer is the most common cancer affecting sub-Saharan African women and is prevalent among HIV-positive (HIV+) individuals. No comprehensive profiling of cancer genomes, transcriptomes or epigenomes has been performed in this population thus far. We characterized 118 tumors from Ugandan patients, of whom 72 were HIV+, and performed extended mutation analysis on an additional 89 tumors. We detected human papillomavirus (HPV)-clade-specific differences in tumor DNA methylation, promoter- and enhancer-associated histone marks, gene expression and pathway dysregulation. Changes in histone modification at HPV integration events were correlated with upregulation of nearby genes and endogenous retroviruses.

Selecting human papillomavirus genotypes to optimize the performance of screening tests among South African women.

Human papillomavirus (HPV) testing is highly sensitive compared to cytology, with the trade-off of being less specific. We investigated whether select combinations of HPV genotypes, ascertained by Linear Array (LA) and Xpert HPV (GX), can optimize sensitivity/specificity trade-offs to detect high-grade cervical intraepithelial neoplasia (CIN2+). In a study in Cape Town, South Africa, 586 women living without and 535 living with HIV, aged 30-65 years, were recruited. Each woman underwent a pelvic exam to collect cervical samples (tested by LA and GX for 14 high-risk HPV genotypes) and underwent colposcopy with histological sampling to determine CIN2+. In multivariable logistic regression of LA results, only HPV genotypes 16, 18, 31, 33, 35, 52, 58 were significantly associated with CIN2+ (P < .05). Xpert includes these seven types along with HPV 45 within three of the test's five channels and we defined these eight types as restricted genotyping (ie 16, 18, 31, 33, 35, 45, 52, 58). Full genotyping was defined as all 14 high-risk types. Sensitivity estimates for full genotyping using LA were similar to that of restricted genotyping: 83.9% (full) vs 79.0% (restricted) in women without HIV and 93.0% (full) vs 88.9% (restricted) in women living with HIV. Specificity estimates improved for restricted vs full genotyping: 87.4% (full) vs 90.8% (restricted) in women without HIV and 63.7% (full) vs 71.4% (restricted) in women living with HIV. To optimize the performance of HPV testing for cervical cancer screening in high-burden, under-resourced settings like South Africa, only HPV 16, 18, 31, 33, 35, 45, 52, 58 could be included to define screen-positive. We recommend the inclusion of HPV45 for its known link to adenocarcinoma.

A Pooled Analysis to Compare the Clinical Characteristics of Human Papillomavirus-positive and -Negative Cervical Precancers.

Given that high-risk human papillomavirus (HPV) is the necessary cause of virtually all cervical cancer, the clinical meaning of HPV-negative cervical precancer is unknown. We, therefore, conducted a literature search in Ovid MEDLINE, PubMed Central, and Google Scholar to identify English-language studies in which (i) HPV-negative and -positive, histologically confirmed cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) were detected and (ii) summarized statistics or deidentified individual data were available to summarize proportions of biomarkers indicating risk of cancer. Nineteen studies including 3,089 (91.0%) HPV-positive and 307 (9.0%) HPV-negative CIN2+ were analyzed. HPV-positive CIN2+ (vs. HPV-negative CIN2+) was more likely to test positive for biomarkers linked to cancer risk: a study diagnosis of CIN3+ (vs. CIN2; 18 studies; 0.56 vs. 0.24; P < 0.001) preceding high-grade squamous intraepithelial lesion cytology (15 studies; 0.54 vs. 0.10; P < 0.001); and high-grade colposcopic impression (13 studies; 0.30 vs. 0.18; P = 0.03). HPV-negative CIN2+ was more likely to test positive for low-risk HPV genotypes than HPV-positive CIN2+ (P < 0.001). HPV-negative CIN2+ appears to have lower cancer risk than HPV-positive CIN2+. Clinical studies of human high-risk HPV testing for screening to prevent cervical cancer may refer samples of HPV test-negative women for disease ascertainment to correct verification bias in the estimates of clinical performance. However, verification bias adjustment of the clinical performance of HPV testing may overcorrect/underestimate its clinical performance to detect truly precancerous abnormalities.

Time to intravenous antibiotic administration (TIbiA) in severe open tibial fractures: Impact of change to national guidance.

INTRODUCTION: Severe open tibial fractures are limb-threatening injuries. Outcomes depend on a complex interplay of patient, injury and treatment factors. 2009 guidelines from the British Orthopaedic Association (BOA) and British Association of Plastic, Reconstructive and Aesthetic Surgeons (BAPRAS) recommend prophylactic intravenous antibiotic administration within three hours of injury. More recent National Institute for Health and Care Excellence (NICE) 2016 guidelines recommend pre-hospital antibiotic administration where possible. This study aimed to analyse the impact of time to antibiotics on development of deep infection. METHODS: Adult acute Gustilo-Anderson 3B open tibial fractures managed at a single UK Major Trauma Centre were reviewed retrospectively over a three-year period, including a period before and after the regional ambulance service introduced a policy of administering pre-hospital intravenous antibiotics to open fractures in 2016. Development of deep infection was recorded as the primary outcome measure. Complete case regression analysis was performed. Time was assessed as a continuous variable and as thresholds with antibiotics received within one or three hours of injury. RESULTS: 156 patients with 159 fractures were included. Following introduction of new guidance in 2016, median time to antibiotics decreased from 180 to 160 min and more patients received pre-hospital antibiotics (2% vs. 33%). Overall, 7.5% developed deep infection (n = 12) within a median follow-up of 26 months. Logistic regression found no relationship between any independent variable, including time to antibiotic administration, and development of deep infection. CONCLUSIONS: There are a variety of factors identified in the literature and in national policies and treatment guidelines as potentially modifiable to reduce the risk of deep infection following open fractures. In this study, time to antibiotic administration was not associated with the risk of developing deep infection. The results of this study demonstrate a low infection rate, which may be due to expedient expert care delivered by a dedicated orthoplastic service in line with national guidance where achievable.

The medial sural artery perforator (MSAP) flap: A versatile flap for lower extremity reconstruction.

BACKGROUND: The medial sural artery perforator (MSAP) flap provides a thin, pliable and durable soft tissue reconstruction with adequate pedicle length and low donor morbidity. It is an ideal choice for small-to-moderate defects of the lower extremity, although it does have limitations. We report our experience of the flap in a three-pronged anatomical, clinical and patient reported outcome-based study. METHODS: Cadaveric fresh frozen lower limbs (n = 10) were used for anatomical dissections to assess pertinent and clinically relevant findings. Data relating to MSAP flaps was collected from a prospectively maintained database over a 2-year period. Both clinical data and modified Enneking scores were analysed. RESULTS: Anatomical study: A mean of 2.1 ± 0.99 perforators arose from the medial sural artery, located 11.9 cm ± 2.07 along the line between the popliteal fossa and medial malleolus. The largest perforator was located 13.58 cm ± 2.01 from the popliteal artery. The distance from the dominant perforator to the first branching point within the gastrocnemius was 7.39 ± 1.50 (range 5-9.2 cm). The short saphenous vein was located on average 3.08 cm ± 0.77 from the dominant perforator. Clinical study: Twenty free and nine pedicled MSAPs were included (n = 29). Open lower limb fractures (n = 18, 62%) and infection (n = 10, 35%) were the most common aetiologies. Defects sites included: foot-and-ankle (n = 12, 55%), knee (n = 9, 31%) and anterior leg (n = 4, 14%). Four patients (14%) required SSG to for donor site coverage. Venous congestion was responsible for partial flap necrosis in 6.9%(n = 2) of patients. All wounds were healed at discharge. At 14 months, the mean Enneking score was 72.5%. All patients were ambulant, 96% returned to work and 87% were using pre-operative footwear. CONCLUSIONS: The MSAP provides robust foot-and-ankle reconstruction, whilst permitting glide when over the knee. Patient satisfaction and functional outcomes are excellent with careful patient selection. Care should be taken to avoid compression or kinking of the large, thin walled veins as the most commonly observed complication was venous congestion. We advocate MSAP as a first choice flap for small-to-moderate foot, ankle or knee defects.

Clinical evaluation of modifications to a human papillomavirus assay to optimise its utility for cervical cancer screening in low-resource settings: a diagnostic accuracy study.

BACKGROUND: HPV-based screen and treat is the recommended approach for cervical cancer screening in low-resource settings, but quite low specificity of human papillomavirus (HPV) testing, particularly in women living with HIV, leads to overtreatment. We evaluated whether HPV type restriction and more stringent cutoffs on Xpert HPV optimise performance characteristics of this assay for screen and treat. METHODS: We recruited HIV-negative and HIV-positive women aged 30-65 years from a primary care facility and a referral colposcopy clinic in Cape Town, South Africa. Women included had no history of any anogenital cancer or treatment for cervical dysplasia, had no hysterectomy, and were not pregnancy at the time of recruitment. All women had cervical samples collected for Xpert HPV (an assay that detects high-risk HPV types in five channels: HPV type 16; HPV types 18 or 45, or both; HPV types 31, 33, 35, 52, or 58, or more than one of these types; HPV types 51 or 59, or both; and HPV types 39, 56, 66, or 68, or more than one of these types) and underwent colposcopy and histological sampling with consensus pathology review. Logistic regression and receiver operating characteristic curves were used to evaluate improvements in specificity attained by modifying cycle threshold cutoffs to define screen-positive results. RESULTS: We recruited 1121 women aged 30-65 years, 586 of whom were HIV-negative and 535 HIV-positive. Sensitivity of detecting cervical intraepithelial neoplasia grade 2 or greater in HIV-negative women using manufacturer-defined cycle threshold cutoffs for all channels was 88·7% (95% CI 83·1-94·3), and specificity was 86·9% (83·4-90·4). Sensitivity was 93·6% (90·0-97·3) and specificity 59·9% (54·1-65·7) in HIV-positive women. Cycle threshold values from channels detecting HPV type 16, HPV types 18 or 45 (or both), and HPV types 31, 33, 35, 52, or 58 (or more than one of these types) were informative to predict cervical intraepithelial neoplasia grade 2 or greater. Shifting cycle threshold cutoffs on these three channels allowing sensitivity to decline to 75-85%, led to specificities of 91·3-95·3% in HIV-negative women and 77·0-85·8% in HIV-positive women. INTERPRETATION: More stringent cycle threshold cutoffs on selected channels in Xpert HPV improve specificity with only modest losses in sensitivity, making this assay an optimal choice for HPV-based screen and treat in settings with a high prevalence of HIV. These modifications can be made from standard output with no need for new engineering. Decision making about performance characteristics of HPV testing can be shifted to programme implementers and cutoffs selected according to resource availability and community preferences. FUNDING: Supported by the National Cancer Institute UH2/3 CA189908.

Approaches to triage optimization in HPV primary screening: Extended genotyping and p16/Ki-67 dual-stained cytology-Retrospective insights from ATHENA.

The objective of our study was to assess the performance of different triage strategies for high-risk human papillomavirus (hrHPV)-positive results utilizing either extended genotyping or a p16/Ki-67 dual-stained cytology (DS) approach, with or without partial genotyping. A subset of women with hrHPV infections participating in the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study were analyzed to determine the number of cervical intraepithelial neoplasia grade 3 or worse (≥CIN3) cases detected, and the absolute risk for ≥CIN3 of each genotype. A clinical utility table was constructed to compare the impact of different triage strategies. In all, 2,339 women with single-genotype hrHPV infections were identified. Among these were 171 ≥CIN3 cases. The U.S. Food and Drug Administration (FDA)-approved algorithm (HPV16/18 positive, or 12-other hrHPV positive and Pap positive, i.e., ≥ atypical squamous cells of undetermined significance) for primary HPV screening detected 132/171 (77.2%) ≥CIN3 cases and required 964 colposcopies (colposcopies per ≥CIN3 ratio: 7.3). An approach that uses DS instead of cytology in the FDA-approved algorithm detected 147/171 (86.0%) ≥CIN3 cases, requiring 1,012 colposcopies (ratio: 6.9). Utilizing DS for triage of all hrHPV-positive women identified 126/171 (73.7%) ≥CIN3 cases, requiring 640 colposcopies (ratio: 5.1). A strategy that detected HPV16/18/31/33/35+ captured 130/171 (76.0%) ≥CIN3 cases, requiring 1,025 colposcopies (ratio: 7.9). Inclusion of additional genotypes resulted in greater disease detection at the expense of higher colposcopy ratios. Substituting cytology with a DS triage approach improved disease detection and the colposcopy detection rate. Further reduction of colposcopy rates can be achieved by using DS without partial genotyping. Extended genotyping strategies can identify a comparable number of cases but requires an increased number of colposcopies.

Risk detection for high-grade cervical disease using Onclarity HPV extended genotyping in women, ≥21 years of age, with ASC-US or LSIL cytology.

OBJECTIVES: There is growing interest in using human papillomavirus (HPV) genotyping as a risk-based triage approach for women with atypical squamous cells-undetermined significance (ASC-US) and low-grade squamous intraepithelial lesions (LSIL) cytology. METHODS: This analysis includes 2807 subjects with ASC-US or LSIL cytology, ≥21 years, from the baseline phase of the Onclarity HPV trial. All women were referred to colposcopy/biopsy. Hierarchical-ranked prevalence and risk values, associated with high-grade cervical disease, were calculated based on extended genotyping. RESULTS: HPV 16 carried the highest risk for cervical intraepithelial neoplasia grade 2 or worse (≥CIN2) in both the ASC-US and LSIL populations. Risk of ≥CIN3 and ≥CIN2 associated with the other 13 genotypes varied somewhat for women with ASC-US and LSIL, however, HPV 31, 18, 33/58, 51 and 52 appear to comprise an intermediate risk band. Risk associated with HPV 35/39/68, 45, and 56/59/66, in either cytology population, was relatively low and beneath the benchmark threshold risk for immediate colposcopy. Restricting the analysis to women 21-24 years, ≥25 years, or ≥30 years produced similar results. CONCLUSIONS: HPV genotyping identified multiple risk bands for ≥CIN3 and ≥CIN2 in the ≥21 year-old ASC-US and LSIL populations. These results support a 1-year follow-up period to preclude immediate colposcopy for ASC-US or LSIL women positive for the lowest-risk HPV genotypes.

A comparison between the Major Trauma Centre management of complex open lower limb fractures in children and the elderly.

INTRODUCTION: Open lower limb fractures can be devastating with outcomes determined by tissue damage and adherence to strictly defined care pathways. Managing such injuries in paediatric and elderly populations presents logistical and technical challenges to achieve best outcomes. Orthoplastic principles were developed mainly in the young adult population whereas requirements for paediatric and elderly patients need further understanding. METHODS: A retrospective analysis was performed on two groups of patients at the extremes of age, with type IIIb (severe) open lower limb fractures, presenting to a Major Trauma Centre (MTC) with orthoplastic services over a six-year period - the first group being under 16 years; the second group being over 65. The timelines of combined surgery to both fix the fracture and flap the soft-tissue defect were strictly observed. Each group were followed-up for a minimum of nine months. Data were analysed according to patient demographics, mechanism of trauma, time to wound excision, time to definitive surgery, fixation technique, soft-tissue reconstruction type, deep infection rate, flap survival, bony union, secondary amputation and functional outcome (Enneking score). RESULTS: 33 paediatric patients and 99 elderly patients were identified. Paediatric: The median age was 12 years. All the children were ASA Grade I. Open tibial fractures were most common (76%) followed by ankle fracture dislocation (12%). The majority were high-energy injuries and were commonly managed with external fixators (or frames) and free flap coverage. Median hospital stay was 12 days, and time to union 114 days, with median Enneking scores of 85%. There was one flap failure and no deep infections. Elderly: The median age was 76 years. ASA grades varied and reflected multiple comorbidities. High-energy injuries required free flaps, while more common, low-energy fragility fractures were covered with loco-regional flaps. Internal fixation with intramedullary nails was most commonly used. Median hospital stay was 13 days, and time to union was 150 days, with median Enneking scores of 70%. There was one flap failure, one deep infection, and one delayed amputation. DISCUSSION: These results reflect both similarities and important differences in managing open fractures in the extremes of age. The specific challenges of each group of patients are discussed, including surgical aspects, but also the importance of orthoplastics infrastructure within the MTC and input from allied professionals to facilitate patient pathways.

HPV infections and cytologic abnormalities in vaccinated women 21-34 years of age: Results from the baseline phase of the Onclarity trial.

OBJECTIVES: Countries with school-based human papillomavirus (HPV) vaccination have seen significant reductions in vaccine-targeted HPV infections, cytologic abnormalities, and high-grade cervical intraepithelial neoplasia (≥CIN2). However, the impact of HPV vaccination in the United States (where vaccination is largely opportunistic) may be less due to lower coverage rates and vaccination in patients at ages beyond the recommended routine vaccination age. METHODS: The Onclarity trial enrolled 33,858 subjects ≥21 years who were screened with cytology and the BD Onclarity HPV Assay. HPV positive women or those with cytologic abnormalities underwent colposcopy and biopsy. The prevalence of HPV, cytologic abnormalities, and ≥CIN2 was compared in a subset of 14,153, vaccinated and unvaccinated women, 21-34 years. Results were compared by vaccination status; Mantel-Haenszel analysis was performed to determine the association between vaccination status and prevalence, adjusting for age. RESULTS: The prevalence of overall HPV, HPV16, 18, 31, and 33/58 were all lower in vaccinated women for each age group; a significant difference (p < 0.001) was observed in vaccinated women for all ages combined. Cytologic low-grade squamous intraepithelial lesion (LSIL) or worse was lower in vaccinated women (p = 0.021), as was ≥CIN2 prevalence associated with HPV 16 or 18 (p = 0.011). CONCLUSIONS: Women with a prior history of HPV vaccination have a lower prevalence of any high-risk HPV, HPV 16, 18, 31, and 33/58; a cytology result of ≥LSIL, and ≥CIN2 associated with HPV 16/18 compared to unvaccinated women. A lower HPV prevalence in older, vaccinated women suggests that "catch-up" vaccination provides benefit.

Stratified risk of high-grade cervical disease using onclarity HPV extended genotyping in women, ≥25 years of age, with NILM cytology.

OBJECTIVES: Increasing evidence suggests that extended human papillomavirus (HPV) genotyping (beyond 16/18) is effective for risk stratification in women with normal cytology. This report provides extended genotyping results, using the BD Onclarity HPV Assay, for individual genotypes HPV16, 18, 31, 45, 51, and 52 ̶ and three pooled genotype results for HPV33/58, 35/39/68, and 56/59/66. METHODS: 27,037 women with normal cytology, ≥25 years, were enrolled into the Onclarity HPV trial during routine screening. Women positive for any HPV genotype were referred to colposcopy/biopsy. Hierarchical-ranked prevalence and risk values, associated with cervical intraepithelial neoplasia, grade 2 or worse (≥CIN2) or ≥CIN3, were calculated based on extended genotyping results. RESULTS: HPV 16 and 31 carried the highest risk for ≥CIN2 (11.6% and 12.1%, respectively) and ≥CIN3 (8.1% and 7.5%, respectively); these genotypes were the most prevalent in both ≥CIN2 (29.6% and 19.3%, respectively) and ≥CIN3 (43.7% and 22.5%, respectively). Of the other 12 genotypes, HPV 18, 33/58, and 52 comprised an intermediate risk band (≥CIN2 risk range: 4.9-6.8%; ≥CIN3 risk range: 3.9-5.0%). Genotypes 45, 51, 35/39/68, and 56/59/66 constituted the lowest risk band for both disease grades (≥CIN2 value risk range: 1.7-3.0%; ≥CIN3 value risk range: 1.2-3.6%). CONCLUSIONS: Extended genotyping stratifies risk for ≥CIN2/3 in the ≥25 year-old, normal cytology population. While baseline HPV 16/31 values exceeded the risk threshold for colposcopy referral, the management of women with normal cytology who were positive for the intermediate- or lower-risk genotypes may evolve based on refined risk estimates as well as clinical factors.