An increase in regulatory T cells in peripheral blood correlates with an adverse prognosis for malignant melanoma patients - A study of T cells and natural killer cells.

Malignant melanoma is a highly immunogenic tumour, and the immune profile significantly influences cancer development and response to immunotherapy. The peripheral immune profile may identify high risk patients. The current study showed reduced levels of CD4+ T cells and increased levels of CD8+ T cells in peripheral blood from malignant melanoma patients compared with controls. Percentages of peripheral CD56dimCD16+ NK cells were reduced and CD56brightCD16-KIR3+ NK cells were increased in malignant melanoma patients. Late stage malignant melanoma was correlated with low levels of CD4+ T cells and high levels of CD56brightCD16-KIR3+ NK cells. Finally, high levels of Tregs in peripheral blood were correlated with poor overall survival and disease-free survival. The results indicate that changes in specific immune cell subsets in peripheral blood samples from patients at the time of diagnosis may be potential biomarkers for prognosis and survival. Further studies will enable clarification of independent roles in tumour pathogenesis.

Efficacy of the intertransverse process block: single or multiple injection? A randomized, non-inferiority, blinded, cross-over trial in healthy volunteers.

INTRODUCTION: The intertransverse process block is increasingly used to ameliorate postoperative pain following a plethora of surgical procedures involving the thoracic wall. Nevertheless, the optimal approach and cutaneous extent of the sensory block are currently unknown. We aimed to further describe the intertransverse process block, single injection versus multiple injection, and we hypothesized that the single-injection intertransverse process block is a non-inferior technique. METHODS: Twelve healthy male volunteers were cross-over randomized to receive either single-injection intertransverse process block with 21 mL ropivacaine 7.5 mg/mL, including two sham injections, at the thoracic level T4/T5 or multiple-injection intertransverse process block with three injections of 7 mL ropivacaine 7.5 mg/mL at the thoracic levels T2/T3, T4/T5 and T6/T7 at the first visit. At the second visit, the other technique was applied on the contralateral hemithorax. A non-inferiority margin of 1.5 anesthetized thoracic dermatomes was chosen. RESULTS: The mean difference (95% CI) in the number of anesthetized thoracic dermatomes was 0.82 (-0.41 to 2.05) pnon-inf<0.01 indicating non-inferiority favoring the single-injection technique.Both techniques anesthetized the ipsilateral thoracic wall and demonstrated contralateral cutaneous involvement to a variable extent. The multiple-injection intertransverse process block anesthetized a significantly larger cutaneous area on the posterior hemithorax and decreased mean arterial pressure at 30 and 60 min postblock application. Thoracic thermography showed no intermodality temperature differences yet compared with baseline temperatures both techniques showed significant differences. CONCLUSIONS: Single-injection intertransverse process block is non-inferior to multiple injection in terms of anesthetized thoracic dermatomes. Both techniques generally anesthetize the hemithoracic wall to a variable extent. EU CLINICAL TRIALS REGISTER: 2022-501312-34-01.

Stage-Specific Risk of Recurrence and Death From Melanoma in Denmark, 2008-2021: A National Observational Cohort Study of 25 720 Patients With Stage IA to IV Melanoma.

Importance: To ensure optimal treatment and surveillance of patients with melanoma, knowledge of the clinical stage-specific risk of recurrence, mortality, and recurrence patterns across the American Joint Committee on Cancer Eighth Edition (AJCC8) substages is needed. Objective: To estimate stage-specific recurrence and melanoma-specific mortality rates, assess absolute stage-specific risks of recurrence and mortality, and describe stage-specific recurrence patterns, including conditional rates. Design: Retrospective cohort study of prospectively collected nationwide population-based registry data. Setting: Nationwide, population-based cohort study. Participants: The 25 720 Danish patients, 18 years or older, diagnosed with first-time stage IA to IV cutaneous melanoma between January 1, 2008, and December 31, 2019, were included and followed up from time of primary treatment until December 31, 2021. Exposures: First diagnosis of stage IA to IV cutaneous melanoma. Main Outcomes: Stage-specific cumulative incidence of recurrence and melanoma-specific mortality, melanoma-specific recurrence-free survival, and assessed absolute stage-specific risks of recurrence and melanoma-specific mortality. Secondary outcomes were stage-specific recurrence patterns, including conditional rates, and melanoma-specific survival. Results: We followed up 25 720 patients for a median of 5.9 years (95% CI, 58.9-59.3 years). Mean age was 59.1 years (95% CI, 58.9-59.3 years). Patients with stage IIB to IIC melanoma were older, had more comorbidities at diagnosis, and had the lowest rate of pathologic staging by sentinel node biopsy (81.6%-87.4%). A total of 10.6% of patients developed recurrence; first recurrence included distant recurrence, alone or with synchronous locoregional recurrence, in 56.6% of patients. We found a comparable risk of recurrence in stages IIIA and IIB (29.7% vs 33.2%) and in stages IIIB and IIC (35.9% vs 36.8%), respectively. Melanoma-specific mortality was comparable between stages IIIA and IIA (13.0% vs 13.6%) and between stages IIIB and IIB (18.4% vs 22.0%), respectively. These risk patterns persisted in cause-specific hazards models. Conclusions and Relevance: This nationwide, population-based cohort study found that the increasing stages of the current AJCC8 staging system do not accurately reflect an increasing risk of recurrence and mortality in melanoma. The high proportion of distant recurrences suggests that hematogenous spread is a more common metastatic pathway than previously assumed, and surveillance with routine functional/cross-sectional imaging should be considered for stages IIB to IV. Future efforts should be put toward developing new tools for risk stratification and determining the survival effect of routine imaging in surveillance.

The intertransverse process block single- or multiple-injection? A study protocol.

BACKGROUND AND AIMS: Intertransverse process (ITP) blocks are applied on the posterior side of the thoracic paravertebral space. The modality is described as being a paravertebral block by proxy, possibly providing a similar analgesic effect as the thoracic paravertebral block. However, systematic evidence on anaesthetised dermatomes and the extent of cutaneous sensory loss following ITP blocks is sparse. This study aims to test the single- versus the multiple-injection ITP block. The primary outcome is the number of anaesthetised thoracic dermatomes for each block type. METHODS: Twelve healthy male volunteers will participate in this randomised, procedure-related, double-blinded, non-inferiority crossover trial after informed consent. Blinded participants will receive either a unilateral single-injection ITP block with 21 mL ropivacaine 7.5 mg/mL including two sham blocks or a unilateral multiple-injection ITP block with 3 × 7 mL ropivacaine 7.5 mg/mL on study Day 1, and the other modality on study Day 2. Block applicants will be blinded from outcome assessment and vice versa. Following block application sensory test by mechanical pinprick and temperature discrimination will be performed. Anterior truncal thermography will be measured three times after block application to compare skin temperature in the mid-clavicular line between the blocked and the contralateral non-blocked hemithorax. In addition, blood pressure changes are measured three times non-invasively. DISCUSSION: The current study will provide substantial knowledge regarding the cutaneous sensory loss of the ITP block. Furthermore, the study might provide insight regarding the possible clinical usage of thermography as a reliable instrument for measuring nerve block efficacy.

Earlier Recurrence Detection Using Routine FDG PET-CT Scans in Surveillance of Stage IIB to IIID Melanoma: A National Cohort Study of 1480 Patients.

BACKGROUND: The effect of routine imaging in melanoma surveillance is unknown. In 2016, Denmark was the first country in the world to implement routine imaging with positron emission tomography-computed tomography with fluorodeoxyglucose (FDG PET-CT) in a nationwide, population-based surveillance program. This study aimed to determine the impact of surveillance with routine FDG PET-CT on hazard, cumulative incidence, and absolute risk of overall, locoregional, and distant recurrence detection in patients with stage IIB to IIID cutaneous melanoma. METHODS: This retrospective, population-based, nationwide cohort study used prospectively collected data from five national health registries to compare hazard, cumulative incidence, and absolute risk of recurrence in patients with cutaneous melanoma diagnosed in 2008-2010 (cohort 1, followed with clinical examinations) and patients with cutaneous melanoma diagnosed in 2016-2017 (cohort 2, followed with clinical examinations and routine FDG PET-CT at 6, 12, 24, and 36 months). RESULTS: The study included 1480 patients with stage IIB to IIID cutaneous melanoma. Cumulative incidences of overall and distant recurrence were higher in cohort 2, with a peak difference at three years (32.3 % vs 27.5 % and 25.8 % vs. 18.5 %, respectively). The hazard of recurrence was higher in cohort 2 during the first two years, with hazard rates for overall and distant recurrence of 1.16 (95 % confidence interval [CI], 0.93-1.44) and 1.51 (95 % CI, 1.16-1.96), respectively. The patterns persisted in absolute risk estimates. CONCLUSIONS: Patients with stage IIB to IIID melanoma followed with routine FDG PET-CT had a 51 % increased hazard of distant recurrence detection within the first two years of surveillance. Future studies must determine whether this earlier recurrence detection translates into improved survival.

Capsulectomy Can Successfully Treat Chronic Encapsulated Breast Seroma: A Case Report.

Chronic encapsulated seroma following breast cancer surgery is a rare entity, and management is challenging. We present clinical and pathologic findings in a patient with previous node-negative breast cancer and an extensive history of chronic bilateral seromas, successfully treated with capsulectomy. This is the first report of fibrous encapsulated breast seroma with bilateral presentation and late onset, following mastectomy with no prior axillary dissection. When managing breast seroma refractory to conventional treatment, the diagnosis of encapsulated seroma should be considered, followed by prompt capsulectomy.

Compression bandaging does not compromise peripheral microcirculation in patients with cellulitis of the lower leg.

Cellulitis ranks among the most frequent infections, and antibiotic treatment is the accepted mainstay of therapy. There is disagreement on the guidelines for the use of compression bandaging as supplementary treatment, and the evidence within the field is scarce. To determine whether compression bandaging impairs microcirculation in patients with cellulitis of the lower leg, thereby having a negative impact on the supply of oxygen, nutritional components, and antibiotics. Adult patients were prospectively enrolled for compression bandaging in addition to antibiotic treatment. The peripheral blood flow rate was measured before and after application of the compression bandage and on the following day. For this, we applied the heat-washout method, which has previously been shown to provide an accurate estimate of peripheral microcirculation. Comparing the blood flow rate before and after application of the compression bandage showed no significant change and therefore no alteration in microcirculation (p = 0.61). Compression bandaging of the lower leg does not impair microcirculation in patients with cellulitis. This strongly indicates that compression bandaging can play a positive role as supportive treatment in addition to standard antibiotic therapy.

The value of ultrahigh resolution OCT in dermatology - delineating the dermo-epidermal junction, capillaries in the dermal papillae and vellus hairs.

Optical coherence tomography (OCT) imaging of the skin is gaining recognition and is increasingly applied to dermatological research. A key dermatological parameter inferred from an OCT image is the epidermal (Ep) thickness as a thickened Ep can be an indicator of a skin disease. Agreement in the literature on the signal characters of Ep and the subjacent skin layer, the dermis (D), is evident. Ambiguities of the OCT signal interpretation in the literature is however seen for the transition region between the Ep and D, which from histology is known as the dermo-epidermal junction (DEJ); a distinct junction comprised of the lower surface of a single cell layer in epidermis (the stratum basale) connected to an even thinner membrane (the basement membrane). The basement membrane is attached to the underlying dermis. In this work we investigate the impact of an improved axial and lateral resolution on the applicability of OCT for imaging of the skin. To this goal, OCT images are compared produced by a commercial OCT system (Vivosight from Michaelson Diagnostics) and by an in-house built ultrahigh resolution (UHR-) OCT system for dermatology. In 11 healthy volunteers, we investigate the DEJ signal characteristics. We perform a detailed analysis of the dark (low) signal band clearly seen for UHR-OCT in the DEJ region where we, by using a transition function, find the signal transition of axial sub-resolution character, which can be directly attributed to the exact location of DEJ, both in normal (thin/hairy) and glabrous (thick) skin. To our knowledge no detailed delineating of the DEJ in the UHR-OCT image has previously been reported, despite many publications within this field. For selected healthy volunteers, we investigate the dermal papillae and the vellus hairs and identify distinct features that only UHR-OCT can resolve. Differences are seen in tracing hairs of diameter below 20 µm, and in imaging the dermal papillae where, when utilising the UHR-OCT, capillary structures are identified in the hand palm, not previously reported in OCT studies and specifically for glabrous skin not reported in any other in vivo optical imaging studies.

Two optical coherence tomography systems detect topical gold nanoshells in hair follicles, sweat ducts and measure epidermis.

Optical coherence tomography (OCT) is an established imaging technology for in vivo skin investigation. Topical application of gold nanoshells (GNS) provides contrast enhancement in OCT by generating a strong hyperreflective signal from hair follicles and sweat glands, which are the natural skin openings. This study explores the utility of 150 nm diameter GNS as contrast agent for OCT imaging. GNS was massaged into skin and examined in four skin areas of 11 healthy volunteers. A commercial OCT system and a prototype with 3 µm resolution (UHR-OCT) were employed to detect potential benefits of increased resolution and variability in intensity generated by the GNS. In both OCT-systems GNS enhanced contrast from hair follicles and sweat ducts. Highest average penetration depth of GNS was in armpit 0.64 mm ± SD 0.17, maximum penetration depth was 1.20 mm in hair follicles and 15 to 40 µm in sweat ducts. Pixel intensity generated from GNS in hair follicles was significantly higher in UHR-OCT images (P = .002) and epidermal thickness significantly lower 0.14 vs 0.16 mm (P = .027). This study suggests that GNSs are interesting candidates for increasing sensitivity in OCT diagnosis of hair and sweat gland disorders and demonstrates that choice of OCT systems influences results.

Anticancer drugs and the regulation of Hedgehog genes GLI1 and PTCH1, a comparative study in nonmelanoma skin cancer cell lines.

Nonmelanoma skin cancer is the most common cancer in humans, comprising mainly basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC proliferation is highly dependent on the Hedgehog signaling pathway. We aimed to investigate a panel of anticancer drugs with known activity against skin cancer for their therapeutic potential in localized, enhanced topical treatment of SCC and BCC. Cytotoxicity profiles for vismodegib, 5-fluorouracil (5-FU), methotrexate (MTX), cisplatin, bleomycin, and vorinostat were established in terms of half maximal inhibitory concentration values in a panel of immortalized keratinocytes (HaCaT), BCC (UWBCC1 and BCC77015), and SCC (A431 and SCC25) cell lines. The impact of treatment on the regulation of Hedgehog pathway target genes (GLI1 and PTCH1), measured by real-time PCR, was compared between UWBCC1 and HaCaT. Varying cell line sensitivity profiles to the examined anticancer drugs were observed. Generally, 24-h drug exposure was sufficient to reduce cell viability. We found that 5-FU, MTX, and cisplatin significantly downregulated the expression of two genes controlled by the Hedgehog pathway (≤25-, 2.9-, and 12.5-fold, respectively, for GLI1 in UWBCC1 cells at 48 h, P<0.0001). The gene regulation showed clear concentration dependence and correlated with cytotoxicity for both 5-FU and MTX. We find a potential for the use of anticancer drugs in localized and enhanced topical treatment of nonmelanoma skin cancer. Of importance in the clinical setting, 24-h drug exposure may be sufficient for significant cytotoxicity for vismodegib, 5-FU, cisplatin, and bleomycin. MTX, 5-FU, and cisplatin may offer particular promise through combined cytotoxicity and downregulation of Hedgehog pathway genes GLI1 and PTCH1.

Matching profiles of masked perpetrators: a pilot study.

Seventeen male volunteers were photographed laterally with and without a tight-fitting balaclava. We then matched these photographs in blind trials. The matches were performed in two separate trials: as side-by-side comparisons, and by using superimposition. In both trials we graded the matches as good, possible and no fit. We found a very high true identification rate of 94% using superimposition, i.e. whether a match judged as good was in fact the correct match. The correct exclusion rate was also high, 94%, when using superimposition, i.e. when no match was found this was in fact correct. However, even though we were often correct in judging the best fit, we often had several possible matches for each case, which means that comparing profiles is not very selective. As such, using superimposition to compare the profile of a masked perpetrator with lateral photos of one or more suspects may indicate the possible matches, and perhaps even the best match, which may be helpful in police investigations, but it would not carry enough weight to be used as evidence per se. This study only focused on the profile. Future studies will use surface laser scans to analyse congruence between masked and unmasked subjects using the whole head.