Intrahepatic cholangiocarcinoma hidden within cancer of unknown primary.

BACKGROUND: Many patients referred with a provisional diagnosis of cancer of unknown primary (pCUP) present with presumed metastatic disease to the liver. Due to the lack of definitive histological markers, intrahepatic cholangiocarcinoma (iCCA) may be overlooked. This study assessed the frequency of iCCA within a pCUP cohort. METHODS: A single UK cancer-center study of sequential patients referred with pCUP from January 2017 to April 2020. Baseline diagnostic imaging was reviewed independently by a radiologist and oncologist; those with radiological features of iCCA (dominant liver lesion, capsular retraction) were identified. RESULTS: Of 228 patients referred with pCUP, 72 (32%) had malignancy involving the liver. 24/72 patients had radiological features consistent with iCCA; they were predominantly female (75%) with an average age of 63 years and 63% had an ECOG PS ≤ 2. The median overall survival (OS) of the iCCA group and the remaining liver-involved CUP group were similar (OS 4.1 vs 4.4 months, p-value = 0.805). Patients, where a primary diagnosis was subsequently determined, had better OS (10.2 months, p-values: iCCA = 0.0279: cCUP = 0.0230). CONCLUSIONS: In this study, 34% of patients with liver-involved pCUP, fulfilled the radiological criteria for an iCCA diagnosis. Consideration of an iCCA diagnosis in patients with CUP could improve timely diagnosis, molecular characterisation and treatment.

MABGEL 1: first phase 1 trial of the anti-HIV-1 monoclonal antibodies 2F5, 4E10 and 2G12 as a vaginal microbicide.

BACKGROUND: Monoclonal antibodies (mAbs) which potently neutralize a broad range of HIV isolates are potential microbicide candidates. To date, topical application of mAbs in humans and their stability in vaginal secretions has not been studied. OBJECTIVES: To assess the pharmacokinetics and safety of the mAbs 2F5, 4E10 and 2G12 when applied vaginally in women. DESIGN: A randomized, double-blind, placebo-controlled phase 1 trial. METHODS: Twenty-eight healthy, sexually abstinent women administered 2.5 g of gel daily for 12 days containing either 10 or 20 mg/g of each mAb (MABGEL) or placebo. Main clinical evaluations and sampling occurred at baseline, 1, 8, and 24 hours post-1st dose and 12 and 36 hours post-12th dose. RESULTS: After adjustment for dilution factors, median levels of 2F5, 4E10 and 2G12 in vaginal secretions at 1 hour post high-dose MABGEL were 7.74, 5.28 and 7.48 mg/ml respectively. Levels of 2F5 and 4E10 declined exponentially thereafter with similar estimated half-lives (4.6 and 4.3 hours). In contrast, 2G12 levels declined more rapidly in the first 8 hours, with an estimated half-life of 1.4 hours during this period. There was no evidence of systemic absorption. There were no significant differences in local or systemic adverse event rates or vaginal flora changes (by qPCR) between active and placebo gel arms. Whilst at least 1 adverse event was recorded in 96% of participants, 95% were mild and none were serious. CONCLUSIONS: Vaginal application of 50 mg of each mAb daily was safe over a 12 day period. Median mAb concentrations detected at 8 hours post dose were potentially sufficient to block HIV transmission.2G12 exhibited more rapid elimination from the human vagina than 4E10 and 2F5, likely due to poor stability of 2G12 in acidic human vaginal secretions. Further research is needed to develop mAb-based vaginal microbicides and delivery systems. TRIAL REGISTRATION: ISRCTN 64808733 UK CRN Portfolio 6470.

A cross-sectional study showing differences in the clinical diagnosis of pelvic inflammatory disease according to the experience of clinicians: implications for training and audit.

OBJECTIVES: Pelvic inflammatory disease (PID) generates diagnostic difficulty even for experienced doctors. Junior doctors and nurses also assess women with symptoms suggestive of PID. We aimed to determine if and how PID diagnoses vary between clinicians with different experience levels. METHODS: Cross-sectional study conducted in U.K. sexual health clinic, nested within a Chlamydia trachomatis (CT), and Neisseria gonorrhoea diagnostic test accuracy study. Proportions and characteristics of women diagnosed clinically with PID by clinicians with varying experience were compared. Outcomes included demographics, presenting symptoms and signs and CT, and CT and/or gonococcal (GC) (CT/GC) positivity. RESULTS: In 3804 women assessed by 36 clinicians, rates of PID, CT and GC were 4.4%, 10.5%, and 2.5%, with no differences between experienced and inexperienced clinicians (p=0.84, p=0.13 and p=0.07, respectively). 63.7% of PID diagnosed by experienced clinicians met Centers for Disease Control and Prevention (CDC) key clinical criteria versus 41.2% by inexperienced; experienced versus inexperienced OR 2.51; 95% CI 1.16 to 5.40). Proportions of CT (CT/GC)-positive PID increased with experience (5.9% (11.8%) to 31.9% (34.1%)); experienced versus inexperienced (OR 3.90; 95% CI 1.12 to 13.5). Percentages of women with CT (CT/GC) who were diagnosed with PID also rose with experience (2.2% (3.9%) to 14.2% (13.7%)), but CT prevalence in PID cases diagnosed by inexperienced clinicians (8.8%) was no greater than in all women they assessed (9.0%), suggesting poorer discriminative skills. CONCLUSIONS: Clinical diagnostic acumen for PID improves with experience. Inexperienced clinicians should focus on the presence of lower abdominal pain with pelvic tenderness and consider additional supportive symptoms, to improve specificity of their diagnoses. TRIAL REGISTRATION NUMBER: ISRCTN 42867448.

Microbicides and HIV prevention: lessons from the past, looking to the future.

PURPOSE OF REVIEW: This review provides an update on developments in HIV microbicide research in the light of recent phase 3 efficacy studies and discusses how lessons learnt from early generation microbicide candidates can assist the development of future agents. RECENT FINDINGS: Results of an interim analysis of a phase 3 trial suggested that cellulose sulfate increased the risk of HIV acquisition compared with placebo. Carraguard, SAVVY and Buffergel also failed to show any HIV protection in human efficacy trials. Recent research has focused on elucidating the reasons behind these failures as well as improving the assessment of safety and efficacy for the next generation of microbicide candidates. PRO 2000 0.5% gel is the only HIV microbicide candidate for which there are preliminary data suggesting efficacy in women. Antiretroviral agents and entry inhibitors may provide the key in the future to developing an effective HIV microbicide both for vaginal and rectal use. SUMMARY: Development of a protective 'barrier' which can be controlled by the receptive partner independent of time of coitus remains a key goal in HIV prevention. A gel or ring-delivered combination of active anti-HIV agents may prove more efficacious than a single agent alone. Challenges in evaluating and manufacturing new candidates must be overcome before a well tolerated, effective, acceptable and affordable microbicide can be produced.