Monkeypox outbreak in Genoa, Italy: Clinical, laboratory, histopathologic features, management, and outcome of the infected patients.

Since May 2022, multiple human Monkeypox cases were identified in nonendemic countries, mainly among men who have sex with men. We aimed to report the features, clinical course, management, and outcome of the Monkeypox cases diagnosed in the Dermatology and Infectious Disease Units of the San Martino Hospital, Genoa, Italy. We performed an observational study of the Monkeypox cases diagnosed from July 1 until August 31, 2022, collecting clinical, laboratory, and histological data. We studied 16 Monkeypox-infected men (14 homosexual, 2 bisexual) with a median age of 37 years. Three were HIV-infected. All patients reported multiple sexual partners and/or unprotected sex in the 2 weeks before the diagnosis. Most patients had prodromal signs/symptoms before the appearance of the skin/mucosal eruption, consisting of erythematous papules/vesicles/pustules in the anogenital area, which tended to erode evolving into crusts and ulcers. Lesions were often associated with local and/or systemic symptoms. Histopathology showed overlapping features in all cases: epidermal ulceration and dermal inflammatory infiltrate consisting of lymphocytes and neutrophils with an interstitial and perivascular/peri-adnexal pattern and endothelial swelling. Concomitant sexually transmitted infections (STIs) (gonococcal/nongonococcal proctitis and anal high-risk human papillomavirus [HR-HPV] infection) were frequent. Four patients were hospitalized, and one received specific treatment. The overall outcome was good. At the follow-up visit, three patients presented skin scars. Our series confirms the features of the current Monkeypox outbreak; however, different from other studies, we found a considerable rate of concomitant STIs, such as anal HR-HPV infection, that should be kept in mind because this persistent infection is the main cause of anal cancers.

Apalutamide-induced lichenoid reaction in a patient with non-metastatic castrate-resistant prostate cancer.

INTRODUCTION: Apalutamide is an oral selective androgen receptor inhibitor, approved by the FDA for the treatment of patients with non-metastatic, castration-resistant prostate cancer (M0 CRPC) at high risk of developing metastases and for patients with metastatic castration-sensitive prostate (mHSPC) in association with androgen deprivation therapy (ADT). In the registration studies, skin reactions were reported among the most common side effects and as an adverse event of special interest. CASE REPORT: Apalutamide-induced rash includes a wide spectrum of different types of skin reactions, but few cases reports and case series have described this adverse event. Here, we report an M0 CRPC patient who experienced a rare skin adverse event, a lichenoid reaction. MANAGEMENT & OUTCOME: After 4 months of therapy with apalutamide, the patient reported dorsal pricking and dry skin. Lichenoid reaction was confirmed histologically and its correlation to the drug was demonstrated after pursuing a multidisciplinary approach. DISCUSSION: To our knowledge, this is one of the first cases of Apalutamide-related lichenoid reaction and this clinical case showed the relevance of a multidisciplinary management when assessing drug-related adverse events. A broader knowledge of the spectrum of drug-related reactions would allow for a better diagnosis and therapy management by both physicians and patients.

Whole-Exome Sequencing and cfDNA Analysis Uncover Genetic Determinants of Melanoma Therapy Response in a Real-World Setting.

Although several studies have explored the molecular landscape of metastatic melanoma, the genetic determinants of therapy resistance are still largely unknown. Here, we aimed to determine the contribution of whole-exome sequencing and circulating free DNA (cfDNA) analysis in predicting response to therapy in a consecutive real-world cohort of 36 patients, undergoing fresh tissue biopsy and followed during treatment. Although the underpowered sample size limited statistical analysis, samples from non-responders had higher copy number variations and mutations in melanoma driver genes compared to responders in the BRAF V600+ subset. In the BRAF V600- subset, Tumor Mutational Burden (TMB) was twice that in responders vs. non-responders. Genomic layout revealed commonly known and novel potential intrinsic/acquired resistance driver gene variants. Among these, RAC1, FBXW7, GNAQ mutations, and BRAF/PTEN amplification/deletion were present in 42% and 67% of patients, respectively. Both Loss of Heterozygosity (LOH) load and tumor ploidy were inversely associated with TMB. In immunotherapy-treated patients, samples from responders showed higher TMB and lower LOH and were more frequently diploid compared to non-responders. Secondary germline testing and cfDNA analysis proved their efficacy in finding germline predisposing variants carriers (8.3%) and following dynamic changes during treatment as a surrogate of tissue biopsy, respectively.

Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma.

ATM germline pathogenic variants were recently found enriched in high-risk melanoma patients. However, ATM loss of heterozygosity (LOH) has never been investigated in melanoma and, therefore, a causal association with melanoma development has not been established yet. The purpose of this study was to functionally characterize 13 germline ATM variants found in high-risk melanoma patients-and classified by in silico tools as pathogenic, uncertain significance, or benign-using multiple assays evaluating ATM/pATM expression and/or LOH in melanoma tissues and cell lines. We assessed ATM status by Immunohistochemistry (IHC), Western Blot, Whole-Exome Sequencing/Copy Number Variation analysis, and RNA sequencing, supported by Sanger sequencing and microsatellite analyses. For most variants, IHC results matched those obtained with in silico classification and LOH analysis. Two pathogenic variants (p.Ser1135_Lys1192del and p.Ser1993ArgfsTer23) showed LOH and complete loss of ATM activation in melanoma. Two variants of unknown significance (p.Asn358Ile and p.Asn796His) showed reduced expression and LOH, suggestive of a deleterious effect. This study, showing a classic two-hit scenario in a well-known tumor suppressor gene, supports the inclusion of melanoma in the ATM-related cancer spectrum.

Mitochondrial apurinic/apyrimidinic endonuclease 1 enhances mtDNA repair contributing to cell proliferation and mitochondrial integrity in early stages of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the leading cause of primary liver cancers. Surveillance of individuals at specific risk of developing HCC, early diagnostic markers, and new therapeutic approaches are essential to obtain a reduction in disease-related mortality. Apurinic/apyrimidinic endonuclease 1 (APE1) expression levels and its cytoplasmic localization have been reported to correlate with a lower degree of differentiation and shorter survival rate. The aim of this study is to fully investigate, for the first time, the role of the mitochondrial form of APE1 in HCC. METHODS: As a study model, we analyzed samples from a cohort of patients diagnosed with HCC who underwent surgical resection. Mitochondrial APE1 content, expression levels of the mitochondrial import protein Mia40, and mtDNA damage of tumor tissue and distal non-tumor liver of each patient were analyzed. In parallel, we generated a stable HeLa clone for inducible silencing of endogenous APE1 and re-expression of the recombinant shRNA resistant mitochondrially targeted APE1 form (MTS-APE1). We evaluated mtDNA damage, cell growth, and mitochondrial respiration. RESULTS: APE1's cytoplasmic positivity in Grades 1 and 2 HCC patients showed a significantly higher expression of mitochondrial APE1, which accounted for lower levels of mtDNA damage observed in the tumor tissue with respect to the distal area. In the contrast, the cytoplasmic positivity in Grade 3 was not associated with APE1's mitochondrial accumulation even when accounting for the higher number of mtDNA lesions measured. Loss of APE1 expression negatively affected mitochondrial respiration, cell viability, and proliferation as well as levels of mtDNA damage. Remarkably, the phenotype was efficiently rescued in MTS-APE1 clone, where APE1 is present only within the mitochondrial matrix. CONCLUSIONS: Our study confirms the prominent role of the mitochondrial form of APE1 in the early stages of HCC development and the relevance of the non-nuclear fraction of APE1 in the disease progression. We have also confirmed overexpression of Mia40 and the role of the MIA pathway in the APE1 import process. Based on our data, inhibition of the APE1 transport by blocking the MIA pathway could represent a new therapeutic approach for reducing mitochondrial metabolism by preventing the efficient repair of mtDNA.

Intestinal Endometriosis: Mimicker of Inflammatory Bowel Disease?

BACKGROUND/AIMS: Endometriosis of the intestinal tract (IE) is thought to mimic inflammatory bowel disease (IBD) both clinically and pathologically but robust data on a large unselected series are missing. Diagnostic problems arise both at colonoscopy as well as on resection specimens for IE when IBD-like features are encountered. The aim was to establish the frequency of IBD-like histology in IE and which type of histological lesions are shared by these two entities. METHODS: One hundred consecutive, unselected cases of surgically resected IE were collected and clinical features and histopathology reviewed and reevaluated. RESULTS: Seventy-five surgical specimens showed no histological alterations except for endometriosis foci. Twenty-two cases showed focal architectural alterations in the absence of significant inflammation. Three cases showed marked inflammatory and architectural mucosal changes making a differential diagnosis with IBD particularly challenging. On follow-up, however, these patients remained symptom-free and with no need for anti-inflammatory therapy after surgical resection of IE. CONCLUSIONS: Diagnostic problems may arise in women who have IBD-like symptoms and histology at colonoscopy but who lack a known diagnosis of endometriosis. Clinicians must be aware that the diagnosis of IBD in patients with IE should be reevaluated over time.

Atypical Spitz Tumor Arising on a Congenital Linear Plaque-Type Blue Nevus: A Case Report With a Review of the Literature on Plaque-Type Blue Nevus.

The plaque-type blue nevus (PTBN) is a rare variant of blue nevus, of which only a few reports are described. A nodular growth within a preexistent PTBN should always alert to the possibility of malignant transformation. The authors report the first case of an atypical Spitz tumor arising on a congenital linear PTBN in a 60-year-old woman. The diagnosis of "atypical Spitz tumor" is here used to describe a microscopic "gray zone" in which it is not possible to differentiate with adequate certainty between a Spitz nevus and a spitzoid melanoma. This report adds to and summarizes the small body of literature describing PTBN and discusses diagnostic and clinical implications.

Histopathologic and transmission electron microscopic findings in monkeypox cutaneous lesions.

Background: a few pathologic and ultrastructural findings of monkeypox skin lesions are available in the literature. To integrate such evidence, we aimed to describe the pathologic features of monkeypox skin lesions and to show monkeypox virions by transmission electron microscopy (TEM). Methods: we studied the cutaneous biopsies of three patients affected by monkeypox during the 2022 monkeypox outbreak. Skin biopsies have been collected only from body sites with a recent laboratory-confirmed mpox virus infection, defined by a polymerase chain reaction (PCR) positive result in specimens taken through skin swabs. Results: in all the samples the epidermis showed keratinocytes ballooning degeneration; perivascular/periadnexal infiltrates composed of neutrophils and lymphocytes were observed in the deep dermis. Immunohistochemistry showed that the infiltrate was mostly composed of CD3+ T-cells. TEM revealed monkeypox virus-like particles in various stages of morphogenesis in the dermis and epidermis; virions were interspersed among keratinocytes and within their cytoplasm. At the intracellular level, virions showed a biconcaveshaped central core, surrounded by lateral bodies and an external membrane; they also appeared as rectangular, brick-shaped, or oval particles with eccentric nucleoids. The histologic features of our skin samples confirmed the few other studies on this topic, except for the eosinophilic inclusions of the cytoplasm of keratinocytes (Guarnieri's bodies). Conclusion: the role of molecular biology is crucial for monkeypox diagnosis but when it is not disposable and/or in doubtful cases, skin biopsy and TEM may be helpful to establish the diagnosis.

Diffuse Melanosis Cutis as the First Sign of Recurrence of Low-Risk Melanoma: Case Report and Systematic Review.

INTRODUCTION: Diffuse Melanosis Cutis (DMC) is a rare and late complication of metastatic malignant melanoma (MM) characterized by progressive pigmentation of skin and sometimes mucous membranes. The distinctive feature is the widespread and progressive deposition of melanin precursors in the dermis. OBJECTIVES: The purpose of this review is to define the clinical and demographic features of DMC and to promote a deeper insight into the clinical manifestation, histological findings, and pathophysiology behind DMC. METHODS: We have conducted a systematic review of the literature on published DMC in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. We also reported a case of DMC secondary to low-risk melanoma. RESULTS: Overall, including our case report, we reported 53 articles described 62 DMC patients. Breslow level of primary melanoma was reported having a mean value of 3.3 mm. The mean survival rate from onset of DMC resulted being 4.36 months. CONCLUSIONS: Among the most widely accepted etiopathogenetic hypotheses are deposition of melanic precursors in the dermis following tumor lysis, melanocyte proliferation induced by neoplastic growth factors, and the presence of diffuse dermal micro-metastases of MM. However, unanimous consensus on the proposed etiopathogenetic models of DMC is still lacking.

Mycobacterium tuberculosis Surgical Site Infection after Cardiac Surgery in the COVID-19 Era: A Case Report.

Infection of surgical wounds with acid-fast bacilli, including tubercle bacilli, is rare, and is poorly described in the literature. We present the case of a 74-year-old male who developed a sternal wound infection after cardiac surgery due to Mycobacterium tuberculosis complex, diagnosed post-mortem. SARS-CoV-2 infection contributed to worsened clinical conditions and surgical site infection. A high degree of suspicion to avoid unnecessary treatments and progression to severe disease with dismal prognosis is necessary in these types of infections.

Reticular Erythematous Mucinosis: Exclusive Involvement of the Axillary Region.

Reticular erythematous mucinosis is a primary cutaneous mucinosis characterized by the presence of erythematous macules, papules, or plaques coalescing into a reticular pattern that typically involves the midline of the chest or back in middle-aged women. Because of this peculiar location, it is also called midline mucinosis. Although atypical disease localizations have been described in the literature, these have always been accompanied by midline involvement. We report a case of reticular erythematous mucinosis with exclusive involvement of the axillary region.

Cancer Patient With Unusual Dyspnea in the COVID-19 Era: Challenging Management of a Rare Cardiac Tumor.

Heart failure symptoms, in particular dyspnea, may be difficult to frame in a patient with cancer. We report the case of an oncological patient whose dyspnea could have been attributable to various causes and whose management was challenging in the context of the coronavirus disease-2019 pandemic. (Level of Difficulty: Beginner.).