The use of Reflectance Confocal Microscopy to diagnose Malignant Melanoma and Lentigo Maligna in the United Kingdom: A Prospective Observational Trial at a Single Centre.

BACKGROUND: Previous work with Reflectance Confocal Microscopy (RCM) imaging has shown high sensitivity and specificity for Malignant Melanoma (MM), but to date there have been no studies on a UK cohort. OBJECTIVES: The study hypothesised that RCM could be used prospectively to accurately diagnose MM and lentigo maligna (LM) in a private UK secondary care, single clinician setting. The study assessed the potential for RCM to be used as a routine screening procedure. METHODS: 597 patients were recruited consecutively where MM or LM featured in the differential diagnosis after clinical examination. A sequential record was made of the clinical, dermoscopic, and RCM findings by a single dermatologist [HS] prior to biopsy. Imaging used the arm-mounted confocal microscope unless access was restricted and required the handheld probe. The likelihood of MM was scored for each modality, each diagnosis building on the last. Histology was assessed by a single blinded histopathologist [JJ]. RESULTS: 734 lesions were included in the analysis, including 86 MM and LM with a median diameter of 7.0 mm. The benign to malignant ratio was 3 to 1 (non-melanocytic malignancies included) and 8.3 to 1 for MM and LM only. The sensitivity and specificity for MM and LM was 62.8% (95% CI 51.70% to 72.98%) and 63.2% (59.27% to 66.84%) for clinical examination; 91.9% (83.95% to 96.66%) and 42.1% (38.14% to 45.88%) for dermoscopy; 94.2% (86.95% to 98.09%) and 83.2% (79.91% to 85.84%) for RCM. For RCM, PPV was 42.4% (38.13% to 46.81%) and NPV was 99.1% (97.87% to 99.60%). CONCLUSION: This study demonstrates that RCM can reliably diagnose MM and is fast enough to be integrated into UK pigmented lesion clinics by dermatologists trained in RCM. "Number needed to treat" dropped from 3.9 with clinical examination to 3.0 with dermoscopy to 1.3 with RCM.

The use of Reflectance Confocal Microscopy to diagnose Basal Cell Carcinoma in the United Kingdom: A Prospective Observational Trial at a Single Centre.

BACKGROUND: Previous work with Reflectance Confocal Microscopy (RCM) imaging has shown high sensitivity and specificity for Basal Cell Carcinoma (BCC), but to date there have been few studies on a UK cohort. OBJECTIVES: The study hypothesised that RCM could be used prospectively to accurately diagnose BCC in a private UK secondary care, single clinician setting. The study assessed the potential for RCM to be used as a routine diagnostic procedure. METHODS: 522 lesions were recruited prospectively where BCC featured in the differential diagnosis after clinical examination. 78 were subsequently excluded. Imaging used the arm-mounted confocal microscope unless access was restricted and required the handheld probe. The likelihood of BCC was scored for each modality, each diagnosis building on the last. Histology was assessed by a single blinded histopathologist [JJ]. RESULTS: 444 lesions from 326 patients were included in the analysis, including 327 BCCs. Median maximum diameter was 6 mm. The sensitivity and specificity for BCC was 69.42% (64.11% to 74.37%) and 52.99% (43.55% to 62.28%) for clinical examination alone; 91.77% (88.25% to 94.51%) and 41.03% (32.02% to 50.50%) plus dermoscopy; 98.78% (96.91% to 99.67%) and 85.47% (77.76% to 91.30%) plus RCM. For RCM PPV was 95.01% (92.14% to 97.07%) and NPV was 96.15% (90.44% to 98.94%). Area under the curve increased from 0.61 to 0.66 to 0.92 as modalities were added. CONCLUSION: This study demonstrates that RCM can, reliably and quickly, diagnose BCC, and that the addition of RCM to dermoscopy permits higher diagnostic accuracy for BCC in the UK. The specificity and sensitivity of the RCM diagnosis did not alter significantly with experience, reflecting the ease and speed of acquiring the skill. CLINICAL TRIAL REGISTRATION: NCT03509415.

The utility of proadrenomedullin and procalcitonin in comparison to C-reactive protein as predictors of sepsis and bloodstream infections in critically ill patients with cancer*.

OBJECTIVES: Infections in critically ill patients continue to impose diagnostic and therapeutic challenges. We seek to investigate the utility of proadrenomedullin and procalcitonin as diagnostic and prognostic biomarkers in febrile critically ill patients with cancer and compare their performance with that of C-reactive protein. DESIGN: Single-center prospective cohort study. SETTING: Tertiary care, academic, university hospital. PATIENTS: One hundred fourteen critically ill patients with cancer with fever. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Blood samples were withdrawn on the day of fever onset and 4 to 7 days thereafter, and the serum proadrenomedullin, procalcitonin, and C-reactive protein levels were measured using the Kryptor technology afterward. Of the 114 adult patients, 27 had bloodstream infections, 36 had localized infections, and the remaining had no infections. The area under the receiver operating characteristic curve for bloodstream infection diagnosis was significantly greater for proadrenomedullin (0.70; 95% CI, 0.59-0.82) and procalcitonin (0.71; 95% CI, 0.60-0.83) compared with C-reactive protein (0.53; 95% CI, 0.39-0.66) (p = 0.021 and p = 0.003, respectively). Receiver operating characteristic analysis also showed that proadrenomedullin (p = 0.005) and procalcitonin (p = 0.009) each had a better performance than C-reactive protein in predicting patients' mortality within 2 months after their fever onset. Regarding patients' response to antimicrobial therapy, proadrenomedullin, procalcitonin, and C-reactive protein levels all significantly decreased from baseline to follow-up in responders (p ≤ 0.002), whereas only proadrenomedullin level significantly increased in nonresponders (p < 0.0001). In patients with documented infections, proadrenomedullin (0.81; 95% CI, 0.71-0.92) and procalcitonin (0.73; 95% CI, 0.60-0.85) each had a greater area under the curve compared with C-reactive protein (0.59; 95% CI, 0.45-0.73) as for as predicting response (p = 0.004 and p = 0.043, respectively). However, for all febrile patients, proadrenomedullin had a significantly greater area under the curve for predicting favorable response than procalcitonin (p < 0.0001). CONCLUSION: In critically ill patients with cancer, proadrenomedullin and procalcitonin both have a promising role in predicting bloodstream infections in a manner more helpful than C-reactive protein. These two biomarkers were superior to C-reactive protein in the prognostic analysis of response to antimicrobial therapy for those patients with documented infections. However, proadrenomedullin was superior to procalcitonin in predicting response in all febrile patients and was unique in showing increased levels among nonresponders.

Pro-adrenomedullin as a novel biomarker for predicting infections and response to antimicrobials in febrile patients with hematologic malignancies.

BACKGROUND: Health professionals and researchers have become increasingly interested in biomarkers that help them in diagnosis of infections with recent growing attention to procalcitonin (PCT) and pro-adrenomedullin (proADM). METHODS: This study compares proADM to PCT as diagnostic and prognostic biomarkers of infection in febrile patients with hematologic malignancies (HMs). From June 2009 to December 2010, 340 febrile HM patients were evaluated for presence of sepsis, systemic inflammatory response syndrome (SIRS), documented infections, and response to antimicrobial therapy. RESULTS: ProADM and PCT levels were measured at onset of fever and then on days 4-7 afterward. Of the 340 patients, 103 had definite sepsis, and 159 had SIRS. Only proADM initial levels were significantly higher in patients with localized bacterial infections than in those with no documented infection (P = .019) and in patients with definite sepsis than those with SIRS (P = .023). The initial proADM and PCT levels were significantly higher in neutropenic patients with BSIs than in those without documented infections (P = .010 and P = . 011, respectively). Follow-up, proADM, and PCT levels decreased significantly in response to antimicrobial therapy in patients with bacterial infections (BSIs or localized; P = .007 and P = .002, respectively). CONCLUSIONS: ProADM and PCT have promising roles in assisting clinicians in managing febrile HM patients. However, proADM appears to have the advantage of predicting localized bacterial infection and differentiating sepsis from SIRS.

Can procalcitonin distinguish infectious fever from tumor-related fever in non-neutropenic cancer patients?

BACKGROUND: Procalcitonin (PCT) has been proposed as a marker of infection and was studied in neutropenic patients. This study investigated its role in non-neutropenic febrile cancer patients (NNCPs). METHODS: Between July 2009 and July 2010, a total of 248 NNCPs with fever were studied. PCT was measured in plasma within 24 hours of fever onset and 4 to 7 days thereafter, using a Kryptor system with a lower limit of quantitation of 0.075 ng/mL. Patients' clinical, microbiological, and radiological data were reviewed to make the diagnosis and were correlated with PCT levels. RESULTS: This study included 30 patients with bloodstream infection (BSI), 60 with localized bacterial infection, 141 with no documented infection, and 8 with tumor-related fever. Most patients (98%) were inpatients or admitted to the hospital during the study. Patients with BSI had significantly higher PCT levels than did those with documented localized infections (P = .048) and no documented infection (P = .011). PCT levels were significantly higher in septic patients than in those without sepsis (P = .012). Patients with stage IV disease or metastasis had significantly higher baseline PCT levels than did those with early stages of cancer (P < .05). PCT levels dropped significantly in patients with bacterial infections in response to antibiotics (P < .0001). CONCLUSIONS: Baseline PCT levels are predictive of BSI and sepsis in NNCPs. They may be predictors of metastasis and advanced cancer. Subsequent decrease in PCT levels in response to antibiotics is suggestive of bacterial infection. Larger trials are needed to confirm the results of this pilot study.

Role of Procalcitonin and Interleukin-6 in Predicting Cancer, and Its Progression Independent of Infection.

Procalcitonin (PCT) and Interleukin-6 (IL-6) have emerged as biomarkers for different inflammatory conditions. The purpose of the study was to evaluate the role of PCT and IL-6 as biomarkers of cancer and its progression in a large cohort of patients. This cross-sectional study included residual plasma samples collected from cancer patients, and control subjects without cancer. Levels of PCT and IL-6 were determined by Kryptor compact bioanalyzer. We identified 575 febrile cancer patients, 410 non-febrile cancer patients, and 79 non-cancer individuals. The median PCT level was lower in control subjects (0.029 ng/ml) compared to cancer patients with stage I-III disease (0.127 ng/ml) (p<0.0001) and stage IV disease (0.190 ng/ml) (p<0.0001). It was also higher in febrile cancer patients (0.310 ng/ml) compared to non-febrile cancer patients (0.1 ng/ml) (p<0.0001). Median IL-6 level was significantly lower in the control group (0 pg/ml) than in non-febrile cancer patients with stages I-III (7.376 pg/ml) or stage IV (9.635 pg/ml) (p<0.0001). Our results suggest a potential role for PCT and IL-6 in predicting cancer in non-febrile patients. In addition, PCT is useful in detecting progression of cancer and predicting bacteremia or sepsis in febrile cancer patients.