Tumor eradication by triplet therapy with BRAF inhibitor, TLR 7 agonist, and PD-1 antibody for BRAF-mutated melanoma.

Programmed death 1 (PD-1)/programmed death-ligand 1 inhibitors are commonly used to treat various cancers, including melanoma. However, their efficacy as monotherapy is limited, and combination immunotherapies are being explored to improve outcomes. In this study, we investigated a combination immunotherapy involving an anti-PD-1 antibody that blocks the major adaptive immune-resistant mechanisms, a BRAF inhibitor that inhibits melanoma cell proliferation, and multiple primary immune-resistant mechanisms, such as cancer cell-derived immunosuppressive cytokines, and a Toll-like receptor 7 agonist that enhances innate immune responses that promote antitumor T-cell induction and functions. Using a xenogeneic nude mouse model implanted with human BRAF-mutated melanoma, a BRAF inhibitor vemurafenib was found to restore T-cell-stimulatory activity in conventional dendritic cells by reducing immunosuppressive cytokines, including interleukin 6, produced by human melanoma. Additionally, intravenous administration of the Toll-like receptor 7 agonist DSR6434 enhanced tumor growth inhibition by vemurafenib through stimulating the plasmacytoid dendritic cells/interferon-α/natural killer cell pathways and augmenting the T-cell-stimulatory activity of conventional dendritic cells. In a syngeneic mouse model implanted with murine BRAF-mutated melanoma, the vemurafenib and DSR6434 combination synergistically augmented the induction of melanoma antigen gp100-specific T cells and inhibited tumor growth. Notably, only triplet therapy with vemurafenib, DSR6434, and the anti-PD-1 antibody resulted in complete regression of SIY antigen-transduced BRAF-mutated melanoma in a CD8 T-cell-dependent manner. These findings indicate that a triple-combination strategy targeting adaptive and primary resistant mechanisms while enhancing innate immune responses that promote tumor-specific T cells may be crucial for effective tumor eradication.

Clinical features of pagetoid spread: Analysis of perianal lesions associated with anal canal adenocarcinoma and perianal primary extramammary Paget disease.

Secondary extramammary Paget disease (s-EMPD) represents anal canal and rectal, bladder, and gynecological cancers, which horizontally extend within the epidermis of the anal and vulvar skin. It is necessary to distinguish this condition from primary extramammary Paget disease (p-EMPD), which occurs primarily in genital and perianal areas. This study aimed to investigate the clinical and histopathological features of these two conditions in the perianal skin and to identify useful features for differentiation. We retrospectively analyzed 16 patients who visited Shinshu University Hospital from 2009 to 2022 and presented with perianal skin lesions and suspected EMPD. Six patients had p-EMPD and 10 had s-EMPD derived from anal canal adenocarcinoma. Regarding clinical features, nine of 10 (90%) of the s-EMPD cases had symmetric skin lesions, whereas all of the p-EMPD cases had asymmetrical lesions (p = 0.0004). Furthermore, assessment of symmetry around the anus showed that s-EMPD had a significantly smaller coefficient of variation than p-EMPD (0.35 and 0.62, respectively; p = 0.048), suggesting that s-EMPD was more symmetric around the anus. The frequency of raised lesions, such as foci or nodules, was nine of 10 (90%) for s-EMPD and one of six (16%) for p-EMPD (p = 0.003). Well-defined tumor borders on the lateral margins were identified in s-EMPD (5/10, 50%); however, they were not identified in p-EMPD (0/6, 0%). The borders tended to be clearer in s-EMPD; however, the difference was not significant (p = 0.078). Based on these findings, we recommend consideration of s-EMPD when anal skin lesions are symmetrical, well-defined, or raised.

Persistent alteration of the skin microbiome in patients with skin rash after receiving EGFR inhibitor treatment.

The pathological mechanism responsible for EGFR inhibitor (EGFRI)-induced skin rash remains unclear. Recent studies reveal associations between skin dysbiosis and skin inflammatory diseases. This study aimed to examine whether skin dysbiosis is associated with EGFRI-induced skin rash. Bacterial swabs were taken from the forehead of 17 cancer patients at baseline and at several time points after EGFRIs initiation, as well as from 20 healthy controls. The skin microbiome was analysed using 16S rRNA sequencing. The severity of the skin rash was assessed using the rash grade. Skin surface parameters (pH, water capacitance, and sebum level) were also measured. Compared with baseline, the abundance of Cutibacterium acnes decreased in 13 of 15 cases, and that of Staphylococcus aureus, Corynebacterium spp., Staphylococcus epidermidis or Proteobacteria increased in 13 of 15 cases after EGFRIs initiation. Skin pH increased significantly in parallel with a decrease in water capacitance after EGFRI initiation. Also, the composition of the skin microbiome of patients with severe rash was significantly different from that of healthy controls. In addition, the skin dysbiosis did not return to baseline during EGFRIs treatment for >1 year. These longitudinal observations indicate that skin dysbiosis is associated with development of skin rash.

The second nationwide surveillance of antibacterial susceptibility patterns of pathogens isolated from skin and soft-tissue infections in dermatology departments in Japan.

The present study compared trends in antimicrobial resistance patterns in pathogens isolated from skin and soft-tissue infections (SSTIs) in Japan with those of a nationwide survey conducted in 2013. Three organisms that caused most of the SSTIs were collected from 12 dermatology departments in medical centers and 12 dermatology clinics across Japan between April 2019 and August 2020. A total of 390 strains, including 267 Staphylococcus aureus, 109 coagulase-negative staphylococci (CNS), and 14 Streptococcus pyogenes strains were submitted to a central laboratory for antimicrobial susceptibility testing. Patient demographic and clinical information was collated. Methicillin-resistant S. aureus (MRSA) was detected in 25.8% (69/267) of the S. aureus strains. The prevalence of MRSA between the present study and the 2013 survey did not differ significantly. Furthermore, there were no significant differences in MIC values and susceptibility patterns of the MRSA strains to other agents, regardless of a history of hospitalization within 1 year or invasive medical procedures. Methicillin-resistant CNS (MRCNS) was detected in 48.6% (53/109) of CNS isolates, higher than the 35.4% prevalence in the 2013 survey. This difference could be attributed to the heterogeneity in the members of the MRCNS, which comprises multiple staphylococci species, between the 2013 and 2019 surveys. However, it was noted that the susceptibility profiles of the MRCNS to each antibiotic were not significantly different from those identified in the 2013 survey. Most strains of S. pyogenes were susceptible to each antibiotic, similar to the 2013 survey. Continuous monitoring of trends in pathogen and susceptibility profiles is important to advise local public health efforts regarding the appropriate treatment of SSTIs.

Changes in the Immune Cell Repertoire for the Treatment of Malignant Melanoma.

Immune checkpoint inhibitors (ICIs) have been used for the treatment of various types of cancers, including malignant melanoma. Mechanistic exploration of tumor immune responses is essential to improve the therapeutic efficacy of ICIs. Since tumor immune responses are based on antigen-specific immune responses, investigators have focused on T cell receptors (TCRs) and have analyzed changes in the TCR repertoire. The proliferation of T cell clones against tumor antigens is detected in patients who respond to treatment with ICIs. The proliferation of these T cell clones is observed within tumors as well as in the peripheral blood. Clonal proliferation has been detected not only in CD8-positive T cells but also in CD4-positive T cells, resident memory T cells, and B cells. Moreover, changes in the repertoire at an early stage of treatment seem to be useful for predicting the therapeutic efficacy of ICIs. Further analyses of the repertoire of immune cells are desirable to improve and predict the therapeutic efficacy of ICIs.

Relapse of Palmoplantar Pustulosis Following COVID-19 Vaccination.

Palmoplantar pustulosis (PPP) is a rare chronic pustular condition that affects the palms and soles. Smoking and focal infections and dental metal allergies are risk factors for PPP development. Here we report a case of a 60-year-old woman who experienced a relapse of PPP after receiving the COMIRNATY vaccine against COVID-19. The patient relapsed after being in remission for seven years. This article shows the possible implications of COVID-19 vaccination related to the relapse of previous diseases and stresses the importance of careful observation of post-vaccination occurrences of skin eruptions, especially in patients having a history of PPP.

Transcription Factors Runx1 and Runx3 Suppress Keratin Expression in Undifferentiated Keratinocytes.

The Runt-related transcription factor (Runx) family has been suggested to play roles in stem cell regulation, tissue development, and oncogenesis in various tissues/organs. In this study, we investigated the possible functions of Runx1 and Runx3 in keratinocyte differentiation. Both Runx1 and Runx3 proteins were detected in primary cultures of mouse keratinocytes. Proteins were localized in the nuclei of undifferentiated keratinocytes but translocated to the cytoplasm of differentiated cells. The siRNA-mediated inhibition of Runx1 and Runx3 expression increased expression of keratin 1 and keratin 10, which are early differentiation markers of keratinocytes. In contrast, overexpression of Runx1 and Runx3 suppressed keratin 1 and keratin 10 expression. Endogenous Runx1 and Runx3 proteins were associated with the promoter sequences of keratin 1 and keratin 10 genes in undifferentiated but not differentiated keratinocytes. In mouse skin, the inhibition of Runx1 and Runx3 expression by keratinocyte-specific gene targeting increased the ratios of keratin 1- and keratin 10-positive cells in the basal layer of the epidermis. On the other hand, inhibition of Runx1 and Runx3 expression did not alter the proliferation capacity of cultured or epidermal keratinocytes. These results suggest that Runx1 and Runx3 likely function to directly inhibit differentiation-induced expression of keratin 1 and keratin 10 genes but are not involved in the regulation of keratinocyte proliferation.

Late Onset of Cardiac Metastasis of a Melanoma following Nivolumab Immunotherapy.

In this report, we present a case of cardiac metastasis of a malignant melanoma originating from the nasal cavity and presenting with cardiac tamponade detected during immunotherapy. The patient was a 66-year-old man diagnosed with malignant melanoma of the right nasal cavity 4 years ago. Two years ago, the size of the melanoma increased making it unresectable; therefore, he was treated thrice with a combination therapy of nivolumab and ipilimumab. Subsequently, the treatment was changed to single-agent nivolumab therapy, which was continuously administered for one and a half years. Imaging evaluation conducted every 3 months showed no distant metastasis. General malaise occurred, and the patient visited our department. He was diagnosed to have cardiac tamponade using echocardiography and was admitted to the emergency department of our hospital. He underwent pericardiocentesis. Computed tomography revealed an irregular mass extending from the right atrium to the inferior vena cava, and malignant melanoma metastasis was diagnosed through catheter biopsy and histology. As the tumor was unresectable, radiotherapy (30 Gy/10 fractions) and dacarbazine administration were performed on the right atrial mass, and pericardial effusion improved.

Clinical history analysis of Japanese melanoma cases and characteristics of melanoma with childhood onset.

It remains debatable whether melanoma with a clinical history of early childhood onset truly arises from a nevus. To clarify the clinical and genetic characteristics of melanoma detected at birth or several years afterwards, 249 melanoma cases seen at Shinshu University Hospital between 2006 and 2015 were retrospectively analyzed. Ten (4.0%) cases (median age 39.5 years, range 19-70 years; male/female 2/8; lesion site, 6 extremities, 2 trunk, 1 head, 1 face; cumulative sun damage [CSD] skin, 9 low-CSD, 1 high-CSD; detection at birth 3) had recorded early childhood onset. Median Breslow's tumor thickness in those cases was 6.0 mm (range: 0.4-17.5 mm). The frequency of lesions detected at <20 years of age was significantly higher for low-CSD melanoma (17.5%) than for high-CSD (3.3%) and acral (0.8%) melanoma. Although melanoma with a history of early childhood onset is rare, the characteristics of such cases should be established since most have progressed to an advanced stage at the initial visit.

Prevalence of Psoriatic Arthritis in Nagano Prefecture, Japan, and Efficacy of the Psoriasis Epidemiology Screening Tool: A Real-World Survey.

Pain, stiffness, and swelling are the main joint symptoms of psoriatic arthritis (PsA); however, they are also common symptoms of other joint diseases. Therefore, it is challenging to distinguish PsA from other joint diseases. To evaluate the prevalence of PsA and the frequency of joint symptoms in psoriasis patients, we conducted a prefecture-wide survey using the Psoriasis Epidemiology Screening Tool (PEST), a patient questionnaire for screening PsA to assess joint symptoms. Data were collected from 764 psoriasis patients, all of whom visited hospitals (55.1%) or clinics (44.9%) in Nagano Prefecture, Japan. The proportion of psoriasis patients with PsA was 6.5% (50 of 764); four patients (1.2%) with PsA were treated in clinics, while 46 patients (10.9%) were treated in hospitals. Based on the responses to the PEST, 18.1% of patients with psoriasis had joint symptoms. In contrast, 73.2% of psoriasis patients with joint symptoms did not have PsA. The PEST showed 52% sensitivity and 93.4% specificity for PsA. In addition, fingernail alterations were common in PsA. The proportion of the population with PsA was lower than reported previously in Japan. This may have been due to the enrollment of a large number of patients treated in clinics. Many patients with PsA were treated at hospitals, which likely reflects the tendency of patients with joint symptoms to receive intensive treatment in hospitals. In addition, based on the lower sensitivity of the PEST in this study, further studies are necessary to establish the validity of the PEST.