The simultaneous occurrence of livedoid vasculopathy and lymphocytic thrombophilic arteritis in six cases.

Lymphocytic thrombophilic arteritis and livedoid vasculopathy may both present with livedo racemosa and ulceration. We present 6 cases with features of both conditions, raising the possibility that they are either closely linked or are part of a spectrum of the same condition.

Complete protection of the BALB/c and C57BL/6J mice against Ebola and Marburg virus lethal challenges by pan-filovirus T-cell epigraph vaccine.

There are a number of vaccine candidates under development against a small number of the most common outbreak filoviruses all employing the virus glycoprotein (GP) as the vaccine immunogen. However, antibodies induced by such GP vaccines are typically autologous and limited to the other members of the same species. In contrast, T-cell vaccines offer a possibility to design a single pan-filovirus vaccine protecting against all known and even likely existing, but as yet unencountered members of the family. Here, we used a cross-filovirus immunogen based on conserved regions of the filovirus nucleoprotein, matrix and polymerase to construct simian adenovirus- and poxvirus MVA-vectored vaccines, and in a proof-of-concept study demonstrated a protection of the BALB/c and C57BL/6J mice against high, lethal challenges with Ebola and Marburg viruses, two distant members of the family, by vaccine-elicited T cells in the absence of GP antibodies.

Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance.

Although cytotoxic T lymphocytes (CTLs) in people infected with human immunodeficiency virus type 1 can potentially target multiple virus epitopes, the same few are recognized repeatedly. We show here that CTL immunodominance in regions of the human immunodeficiency virus type 1 group-associated antigen proteins p17 and p24 correlated with epitope abundance, which was strongly influenced by proteasomal digestion profiles, affinity for the transporter protein TAP, and trimming mediated by the endoplasmatic reticulum aminopeptidase ERAAP, and was moderately influenced by HLA affinity. Structural and functional analyses demonstrated that proteasomal cleavage 'preferences' modulated the number and length of epitope-containing peptides, thereby affecting the response avidity and clonality of T cells. Cleavage patterns were affected by both flanking and intraepitope CTL-escape mutations. Our analyses show that antigen processing shapes CTL response hierarchies and that viral evolution modifies cleavage patterns and suggest strategies for in vitro vaccine optimization.

Impact of place of residence, frailty and other factors on rehabilitation outcomes post hip fracture.

BACKGROUND: Following hip fracture surgery, patients from residential care are frequently excluded from inpatient rehabilitation. We aimed to assess the impact of place of residence and other factors such as frailty on rehabilitation outcomes after hip fracture surgery. METHODS: Retrospective cohort study. Outcome measures included Functional Independence Measure efficiency, discharge destination and recovery of pre-fracture mobility. Univariable and multivariable linear or logistic regression analyses were performed. SETTING: One general rehabilitation and two geriatric evaluation and management wards in a large public tertiary teaching hospital. PARTICIPANTS: A total of 844 patients who underwent inpatient rehabilitation after hip fracture surgery from 2010 to 2018. RESULTS: There were 139 (16%) patients from residential care. Being from residential care was not an independent predictor of poor outcomes. Premorbid frailty (Clinical Frailty Scale) was the strongest independent predictor of poorer Functional Independence Measure efficiency, inability to recover pre-fracture mobility and return to community dwelling. Dementia and delirium were also independently predictive of poor outcomes across all measures. Age > 90 years was independently predictive of inability to recover pre-fracture mobility and return to community dwelling. CONCLUSION: Being from residential care is not independently associated with poor outcomes following inpatient rehabilitation after hip fracture surgery and should not be the basis for excluding these patients from rehabilitation. Major predictors of poorer outcomes include premorbid frailty, dementia, delirium and age > 90 years. If able and motivated, those with potentially reversible functional limitations should be given the opportunity to participate in inpatient rehabilitation as even small gains can have a significant impact on quality of life.

Lymphocytic thrombophilic arteritis and cutaneous polyarteritis nodosa: Clinicopathologic comparison with blinded histologic assessment.

BACKGROUND: Lymphocytic thrombophilic arteritis (LTA), or macular lymphocytic arteritis, is defined by a primary lymphocytic vasculitis. However, the nosology of LTA has been controversial, with speculation that it may represent an indolent non-nodule-forming variant of cutaneous polyarteritis nodosa (cPAN). OBJECTIVE: This study compares the clinicopathologic features of patients with LTA or cPAN to assess if these conditions should be considered distinct entities. METHODS: This is a cross-sectional study of all LTA and cPAN cases at a single tertiary center using prospectively collected clinical data and blinded histologic assessment. RESULTS: The study included 17 patients with LTA and 13 patients with cPAN. Clinically, cases of LTA were distinguished by a more widespread pattern of livedo racemosa, which was noninfiltrated and asymptomatic. In contrast, cPAN was associated with localized starburst livedo, purpura, and episodic features including nodules, pain, and large inflammatory ulcers. When patients were separated according to the presence (>5%) or paucity (≤5%) of neutrophils on blinded histology review, they had distinct clinical features and differences in disease course. LIMITATIONS: This was a single-center study. CONCLUSION: Our data support the classification of LTA and cPAN as separate entities rather than a spectrum of the same disorder and highlight the importance of clinicopathologic correlation in distinguishing these conditions.

The anatomic distribution of cutaneous melanoma: A detailed study of 5141 lesions.

BACKGROUND/OBJECTIVES: There is evidence that cutaneous melanomas at different anatomic sites present with distinctive clinicopathologic features. We examined the anatomic distribution of cutaneous melanoma and its variation by patient characteristics, subtype and Breslow thickness, using high-resolution anatomic site data. METHODS: A cross-sectional study was performed of all primary cutaneous melanoma cases managed at a tertiary referral centre, analysing prospectively collected clinical data across 50 anatomic subsites. RESULTS: The study included 5141 in situ or invasive melanomas; most were invasive (76.2%), and the median Breslow thickness of invasive lesions was 1.0 mm. Superficial spreading (57.2%), lentigo maligna (20.8%) and nodular (12.2%) were the most common histopathological subtypes. Sun-exposed sites such as the female nose and cheek, the male ear, as well as the upper back in both sexes had the highest incidence of melanoma per unit area. When compared to the posterior forearm, the scalp, ear, preauricular, perioral, subungual and plantar sites had thicker invasive melanomas (each P < 0.05). The peri-auricular, ear and cheek had the highest incidence of nodular melanoma per unit area. There were subtype-, age- and sex-specific differences in melanoma anatomic distribution. CONCLUSION: Melanoma most commonly arises in sun-exposed facial areas, as well as the upper back. Increased thickness is found for melanoma in acral and many head and neck sites. Nodular melanoma is more likely to occur in head and neck sites including the peri-auricular area, ear and cheek. Clinicians should carefully assess these sites during skin examinations.

Acral lentiginous melanoma: Clinicopathologic and survival differences according to tumour location.

BACKGROUND/OBJECTIVES: Acral lentiginous melanoma (ALM) is a melanoma subtype associated with atypical locations on the hands and feet and advanced disease at diagnosis. There is a limited understanding of whether the survival is similar for nail, non-nail, lower limb and upper limb ALM patients. We therefore explored clinicopathologic characteristics and melanoma-specific survival of ALM patients according to tumour location. METHODS: A prospectively collected cohort study was performed of all primary invasive cutaneous acral lentiginous melanomas with known thickness and tumour location reviewed at a tertiary referral centre over 21 years. RESULTS: A total of 101 ALM patients were reviewed from 1994 until 2016. The majority of cases (82/101) occurred on the feet. Hand ALMs were thicker and more likely to be ulcerated than feet ALMs (P = 0.05 and 0.02, respectively); however, survival was not statistically different between these two groups (univariate HR 0.48 P = 0.11, 95% CI, 0.20-1.17; multivariate HR 0.67 P = 0.40, 95% CI, 0.27-1.69, respectively). Non-nail ALM patients had longer survival when compared to nail ALM on univariate analysis (HR 0.40, 95% CI, 0.17 to 0.90) which was accounted for by Breslow thickness and ulceration (multivariate HR 0.56, 95% CI, 0.24 to 1.34). CONCLUSIONS: The reduced melanoma-specific survival in nail ALM patients was likely due to their greater thickness and ulceration. Although hand ALMs are thicker and more frequently ulcerated, this is likely due to the higher proportion of nail ALMs present in this location.

Anatomic location of primary melanoma: Survival differences and sun exposure.

BACKGROUND: Anatomic location of melanoma has been shown to independently influence melanoma-specific survival (MSS). OBJECTIVE: We aimed to compare the MSS of specific anatomic subsites and between chronically, intermittently, and rarely sun-exposed sites. METHODS: A prospective cohort study was performed of primary invasive cutaneous melanomas with known thickness and location reviewed at a tertiary referral center over 21 years. RESULTS: Overall, 3570 primary cutaneous invasive melanoma cases were included. After adjustment for clinicopathologic variables (including thickness, ulceration, mitotic rate, sex, age, and subtype), posterior scalp melanoma was associated with worse MSS (hazard ratio [HR], 2.46; 95% confidence interval [CI], 1.38-4.40) compared with the upper back, whereas melanoma on the thighs, forearms/hands, and anterior upper arms had better MSS. Intermittent (HR, 0.56; 95% CI, 0.41-0.76) and chronically sun-exposed sites (HR, 0.70; 95% CI, 0.51-0.96) had improved survival compared with rarely exposed sites on multivariate analysis. LIMITATIONS: Potential selection bias of a tertiary referral center selecting for advanced cases. CONCLUSION: Altered MSS in the posterior scalp, thighs, forearms, hands, and anterior upper arms appears to be independent of clinicopathologic factors. Results were similar for both sexes and age groups. The posterior scalp should be considered a poor prognosis site.

Clinically amelanotic or hypomelanotic melanoma: Anatomic distribution, risk factors, and survival.

BACKGROUND: The recognition and diagnosis of clinically amelanotic or hypomelanotic melanoma is a challenge. OBJECTIVE: This study aimed to examine the anatomic distribution and risk factors associated with clinically amelanotic or hypomelanotic melanoma and compare the survival of patients with clinically amelanotic or hypomelanotic melanoma with that of patients with pigmented melanoma. METHODS: A prospective cohort study of all cases of primary invasive melanoma managed at a tertiary referral center was performed. RESULTS: There were a total of 3913 invasive melanomas, and 384 (9.8%) were clinically amelanotic or hypomelanotic. Skin phototype I; red as well as blonde hair color; actinic keratoses; nodular, desmoplastic, and lentigo maligna subtype; increased Breslow thickness; and mitoses were independently associated with amelanotic or hypomelanotic melanoma (P < .05). After adjustment for subtype and thickness, the face, ears, lateral aspect of the neck, upper portion of the arm, posterior aspect of the forearm, dorsal aspect of the hand, and anterior aspect of the lower portion of the leg were associated with increased odds of amelanotic or hypomelanotic melanoma when compared with the upper portion of the back (P < .05). Mortality risk from melanoma appeared greater for amelanotic or hypomelanotic melanoma than for pigmented melanoma (hazard ratio, 1.5; 95% confidence interval, 1.1-2.1) but was similar once Breslow thickness was taken into account. LIMITATIONS: Single tertiary referral center. CONCLUSION: Although clinically amelanotic or hypomelanotic melanoma can occur on all body sites, it is more common on chronically sun-exposed areas. Clinicians should have an increased index of suspicion in patients with a sun-sensitive skin phenotype, red hair, and associated actinic keratoses.

HIV-1 Conserved Mosaics Delivered by Regimens with Integration-Deficient DC-Targeting Lentiviral Vector Induce Robust T Cells.

To be effective against HIV type 1 (HIV-1), vaccine-induced T cells must selectively target epitopes, which are functionally conserved (present in the majority of currently circulating and reactivated HIV-1 strains) and, at the same time, beneficial (responses to which are associated with better clinical status and control of HIV-1 replication), and rapidly reach protective frequencies upon exposure to the virus. Heterologous prime-boost regimens using virally vectored vaccines are currently the most promising vaccine strategies; nevertheless, induction of robust long-term memory remains challenging. To this end, lentiviral vectors induce high frequencies of memory cells due to their low-inflammatory nature, while typically inducing only low anti-vector immune responses. Here, we describe construction of novel candidate vaccines ZVex.tHIVconsv1 and ZVex.tHIVconsv2, which are based on an integration-deficient lentiviral vector platform with preferential transduction of human dendritic cells and express a bivalent mosaic of conserved-region T cell immunogens with a high global HIV-1 match. Each of the two mosaic vaccines was individually immunogenic. When administered together in heterologous prime-boost regimens with chimpanzee adenovirus and/or poxvirus modified vaccinia virus Ankara (MVA) vaccines to BALB/c and outbred CD1-Swiss mice, they induced a median frequency of over 6,000 T cells/106 splenocytes, which were plurifunctional, broadly specific, and cross-reactive. These results support further development of this vaccine concept.

Lymphocytic thrombophilic arteritis complicated by systemic involvement.

Lymphocytic thrombophilic arteritis (LTA) is a recently described entity defined by primary lymphocytic vasculitis; it typically has a chronic indolent course. We describe a patient who presented with clinical and histological findings consistent with LTA and later developed bilateral focal testicular infarcts as well as an acute median nerve neuropathy.

Three cases of lymphocytic thrombophilic arteritis presenting with an annular eruption.

We describe three patients who presented with a striking erythematous non-blanching annular eruption and features of lymphocytic thrombophilic arteritis (LTA), with a prominent lymphocytic vasculitis involving deep dermal vessels. Lymphocytic inflammation was also evident in the superficial vessels and one patient had small superficial ulcers over the ankle area resembling livedoid vasculopathy (LV). Multiple biopsies demonstrated a persistent absence of neutrophils in the infiltrate consistent with a lymphocytic process. In addition to highlighting the annular morphology as a novel presentation of LTA, these cases suggest a possible relationship between LV and LTA and support the notion that they are distinct from neutrophilic vasculitides such as cutaneous polyarteritis nodosa.

Retrospective audit of patients referred for further treatment following Mohs surgery for non-melanoma skin cancer.

BACKGROUND/OBJECTIVES: To describe the characteristics, subsequent management and outcomes of patients referred for further management following Mohs micrographic surgery (MMS) for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). METHODS: Retrospective analysis of patients referred to a quaternary cancer centre from 2000 to 2015. RESULTS: In total, 83 lesions in 82 patients were referred for further management; 52 (62%) were SCC and 80 (96%) were located in the head and neck. Reasons for referral included high-risk disease for consideration for adjuvant radiotherapy (37/83, 45%), inadequate resection (28/83, 34%) or recurrence following previous MMS (15/83, 17%). Fewer than 40% of the 69 referrals received from MMS surgeons included photos or an operative report and diagram. There was discordance in pathology opinion in 11 (13%) of cases. Histopathology from MMS was reviewed in eight cases and there was discordance with the in-hospital pathology opinion in six of these. In-hospital re-excision was performed in 19 cases and in five of these the pathology report on the paraffin-sectioned re-excised tissue was discordant with prior MMS assessment. Significantly, two cases were associated with a misinterpretation of lymphocytic infiltrate as residual disease in patients with chronic lymphocytic leukaemia (CLL). CONCLUSION: This study highlights some of the challenges and limitations of MMS. Early referral for multidisciplinary management is recommended when MMS resection margins are inadequate or uncertain, especially for high-risk SCC. We recommend that referrals be accompanied by histological material, as well as a detailed report with operative photos and diagrams. CLL can pose an intraoperative diagnostic challenge. Discrepancies in the interpretation of MMS slides present an opportunity for improvement, and our findings support the role of ongoing quality assurance programs.

Novel Conserved-region T-cell Mosaic Vaccine With High Global HIV-1 Coverage Is Recognized by Protective Responses in Untreated Infection.

An effective human immunodeficiency virus type 1 (HIV-1) vaccine is the best solution for halting the acquired immune deficiency syndrome epidemic. Here, we describe the design and preclinical immunogenicity of T-cell vaccine expressing novel immunogens tHIVconsvX, vectored by DNA, simian (chimpanzee) adenovirus, and poxvirus modified vaccinia virus Ankara (MVA), a combination highly immunogenic in humans. The tHIVconsvX immunogens combine the three leading strategies for elicitation of effective CD8(+) T cells: use of regions of HIV-1 proteins functionally conserved across all M group viruses (to make HIV-1 escape costly on viral fitness), inclusion of bivalent complementary mosaic immunogens (to maximize global epitope matching and breadth of responses, and block common escape paths), and inclusion of epitopes known to be associated with low viral load in infected untreated people (to induce field-proven protective responses). tHIVconsvX was highly immunogenic in two strains of mice. Furthermore, the magnitude and breadth of CD8(+) T-cell responses to tHIVconsvX-derived peptides in treatment-naive HIV-1(+) patients significantly correlated with high CD4(+) T-cell count and low viral load. Overall, the tHIVconsvX design, combining the mosaic and conserved-region approaches, provides an indisputably better coverage of global HIV-1 variants than previous T-cell vaccines. These immunogens delivered in a highly immunogenic framework of adenovirus prime and MVA boost are ready for clinical development.

Pentoxifylline: An effective therapy for necrobiosis lipoidica.

Necrobiosis lipoidica (NL) is a rare chronic inflammatory granulomatous skin disorder that remains challenging to treat. Here we report three patients at different stages of disease successfully treated with pentoxifylline, a haemorrheological and anti-inflammatory agent. We demonstrate for the first time that early stage NL may be completely reversible with this treatment. Our findings are also consistent with previous isolated reports showing the effectiveness of pentoxifylline in treating ulcerative NL.

Treatment of nodular vasculitis with colchicine.

Nodular vasculitis (NV) refers to a chronic relapsing lobular panniculitis that is thought to be a hypersensitivity reaction to antigenic triggers. While it is commonly associated with tuberculosis, in many cases no underlying cause is found and the condition is difficult to manage. Here, we report three patients with refractory idiopathic NV effectively treated with colchicine, leading to a significant improvement or complete resolution of their symptoms. Colchicine was successfully used as a steroid-sparing agent, and in one patient its cessation was associated with a flare of disease.

APOBEC3G-induced hypermutation of human immunodeficiency virus type-1 is typically a discrete "all or nothing" phenomenon.

The rapid evolution of Human Immunodeficiency Virus (HIV-1) allows studies of ongoing host-pathogen interactions. One key selective host factor is APOBEC3G (hA3G) that can cause extensive and inactivating Guanosine-to-Adenosine (G-to-A) mutation on HIV plus-strand DNA (termed hypermutation). HIV can inhibit this innate anti-viral defense through binding of the viral protein Vif to hA3G, but binding efficiency varies and hypermutation frequencies fluctuate in patients. A pivotal question is whether hA3G-induced G-to-A mutation is always lethal to the virus or if it may occur at sub-lethal frequencies that could increase viral diversification. We show in vitro that limiting-levels of hA3G-activity (i.e. when only a single hA3G-unit is likely to act on HIV) produce hypermutation frequencies similar to those in patients and demonstrate in silico that potentially non-lethal G-to-A mutation rates are ∼10-fold lower than the lowest observed hypermutation levels in vitro and in vivo. Our results suggest that even a single incorporated hA3G-unit is likely to cause extensive and inactivating levels of HIV hypermutation and that hypermutation therefore is typically a discrete "all or nothing" phenomenon. Thus, therapeutic measures that inhibit the interaction between Vif and hA3G will likely not increase virus diversification but expand the fraction of hypermutated proviruses within the infected host.