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Pure seminomas represent the majority of testicular germ cell tumors and accurate diagnosis and staging require an accurate sampling of radical orchiectomy specimens. The aim of our study is to find the most informative gross sampling method for orchiectomy specimens. We performed the extensive sampling of 88 radical orchiectomy specimens embedding in their entirety testicular hilum, rete testis, hilar soft tissue, and spermatic cord. We examined the impact of this procedure on tumor stage, prognostic parameters (lymphovascular invasion and infiltration of rete testis, epididymis, tunica vaginalis, and spermatic cord), and their relationship with recurrence. Eighty-eight seminomas from 88 radical orchiectomies were sampled. Seventy-seven cases (87.5%) presented as clinical stage I and 11 cases (12.5%) as clinical stage II. The follow-up period range was 18-54 months and 82 patients (93.2%) had a minimum of 2-year follow-up. Tumor size ranged from 0.4 to 16 cm (mean 3.6) requiring a mean of 7.1 sections for entire tumoral sampling. Epididymis required 2 to 8 sections (mean 3.3), and hilum and hilar soft tissues 2 to 9 sections (mean 3.4). Epididymal infiltration and lymphovascular invasion resulted significant at multivariate analysis generating a receiver operating characteristic (ROC) curve with area under curve of 0.778. All the other parameters (except for pagetoid rete testis infiltration) were significant to predict metastasis only at univariate analysis. Extensive sampling of radical orchiectomy specimens does not improve the accuracy of staging in pure seminomas. Lymphovascular invasion and epididymal infiltration are useful to predict metastasis.

Summary Sinonasal teratocarcinosarcoma is a rare aggressive malignant tumor with a primary setting involving the nasal cavity followed by the ethmoid sinus and maxillary sinus. It accounts for approximately 3% of all head and neck cancers and less than 1% of all tumors. Nasal obstruction, recurrent epistaxis and headache represent the typical clinical presentation. Imaging shows the presence of a mass in the nasal cavity. The treatment usually consists of surgery and adjuvant intensity modulated radiotherapy. The rarity and the variability of the histological features make its diagnosis particularly difficult. In this paper, we report a case of sinonasal teratocarcinosarcoma in a 62-year-old male treated with a multidisciplinary approach. As an alternative to intensity modulated radiotherapy, we proposed proton beam therapy for the first time. The patient benefited from the new and personalized protocol that provided excellent results and few adverse effects. At 45 months follow-up there is no evidence of relapse and the patient is in good health.

541 Background: PURE-01 trial enrolled 155 patients who received 3 cycles of pembrolizumab (IO) every 3 weeks before radical cystectomy. We compared tumor-microenvironment immune markers expression in pre- and post-IO TURB specimens in complete/major and non-responders to identify features associated with pathologic response. Methods: We evaluated pre-IO TURB samples of 18 complete responders (CR: ypT0), 6 major responders (MR: ypTa/ypT1) and 19 non-responders (NR: ypT2/ypT3, N0 or N+) and post-IO specimen of 7 CR, 3 MR and 14 NR. Immunohistochemistry analysis for lymphocytes (CD3, CD8, CD20), macrophages (CD68, CD163), immune checkpoints (PD1, PD-L1) and HLA molecule (MHC-I, HLA-DR, B2M) was performed. A semiquantitative count was made on all samples by 3 expert pathologists and a quantitative whole-slide digital evaluation was performed using QuPath (v.0.3) to assess cell density (cells per mm2) and expression of immune checkpoint and HLA molecules. Results: Semiquantitative count showed that seven markers (CD8, CD163, stromal or tumor PD-L1, HLA-DR and B2M on tumor cells) were significantly more expressed on TURB lesions from responders (CR + MR or CR only) compared to NR (N0 or N+) (p-value range: 0.001 to 0.048). In addition to such markers, patients achieving a CR, compared to NR, showed significantly higher expression of CD68 and CD163, of PD-1 on lymphocytes, as well as of tumor MHC-I molecules. Comparison of lesions from patients with CR vs MR revealed significant differences for CD3, CD163, PD-1 and MHC-I, all these markers being more frequently expressed on the former group compared to the latter. Digital pathology analysis confirmed this results on whole-slide evaluation showing higher density of CD8, CD163, PD-L1 and PD-1, and a higher expression B2M, MHC-I and HLA-DR (p-value range: 0.02 to 0.002) in responders. Moreover, N0 patients showed higher expression of PD-L1 and HLA-DR compared to N+ patients. Comparison of pre- and post-IO samples from NR patients showed an increased density of CD8 and CD20 cells (p-value: 0.04 and 0.01), and a decrease of CD163 and HLA-ABC (p-value: 0.003 and 0.02) expressing cells in the post-therapy samples. Conclusions: The tumor immune microenvironment of pre-therapy TURB lesions of patients achieving a complete or major pathologic response after neoadjuvant pembrolizumab shows significant enrichment for T cells and myeloid cells, for stromal or tumor PD-L1 as well as increased MHC-I expression on tumor cells compared to lesions from non responders. Post-IO surgical samples of NR patients showed downregulation of HLA-Class I antigens, in spite of increased CD8 and CD20 density. Clinical trial information: NCT02736266 .

The authors will present a comprehensive account of the neurological aspects of SARS-CoV-2 infection. The aim is to provide a practical clinical book which will serve as a guide for clinicians from all specialties involved in the management of COVID-19 patients. The authors share the extensive clinical experience gained in major hospitals in Lombardy, the first European region to face the COVID-19 emergency in 2020. All are recognized international experts in their respective fields and have been involved in the management of COVID-19 cases from the very beginning of the Italian SARS-CoV-2 outbreak. The text begins with a description of pathobiological and pathophysiological aspects related to the involvement of the nervous system, moving on to the discussion of the neurological complications observed in COVID-19 patients; these range from central to peripheral symptoms, and can occur in the acute or post-acute phases of the disease. Further topics are: neuropathology, seizures and EEG, neuroimaging, delirium, encephalomyelitis, stroke, psychopathology and psychiatry, neuropsychology and cognitive impairment, neuromuscu-lar disorders, and the impact of COVID-19 on other pre-existing neurological disorders. In addi-tion, the book will discuss the new developments in teleneurology approaches, which have been a direct response to the ongoing pandemic. Finally, the possible neurological complications of the COVID-19 vaccines and the neurological complications in children will be considered.Each chapter will present a critical review of the existing literature concerning the specific subject matter, followed by practical clinical recommendations, as well as personal considerations based on the experience gained by each author during the course of the COVID-19 pandemic.Neurology of COVID-19 will be an original and innovative reference book for clinicians of all the specialties involved in the management of patients with SARS-CoV-2 infection. ________________________________________________ List of chapters ________________________________________________

Generalized Arterial Calcification of Infancy (GACI) is a rare disease inherited in a recessive manner, with severe and diffuse early onset of calcifications along the internal elastic lamina in large and medium size arteries. The diagnosis results are from clinical manifestations, imaging, histopathologic exams, and genetic tests. GACI is predominantly caused by biallelic pathogenic variant in the ENPP1 gene (GACI1, OMIM#208000) and, to a lesser extent, by pathogenic variants in the ABCC6 gene (GACI2, OMIM#614473). We present a novel variation in the ENPP1 gene identified in a patient clinically diagnosed with GACI and confirmed by genetic investigation and autopsy as GACI type 1. The sequence analysis of the patient’s ENPP1 gene detected two heterozygous variants c.1412A>G (p.Tyr471Cys) and c.1715T>C (p.Leu572Ser). The variant c.1715T>C (p.Leu572Ser) has not been described yet in the literature and in mutation databases. A genetic analysis was also carried out for the parents of the newborn; the heterozygous pathogenic variant c.1412A>G (p.Tyr471Cys) was detected in the mother’s ENPP1 gene, and a sequence analysis of the father’s ENPP1 gene revealed the novel heterozygous variant c.1715T>C (p.Leu572Ser). Our results showed that the variant c.1715T>C (p.Leu572Ser) may have a pathogenic role in the development of GACI type1 (GACI1, OMIM#208000), at least when associated with the pathogenic c.1412A>G (p.Tyr471Cys) variant. The identification of novel mutations potentially enabled genotype/phenotype associations that will ultimately have an impact on clinical management and prognosis for the disease.

Simple Summary Vulvar squamous cell carcinoma (VSCC) is the most frequent malignant vulvar tumor, with a peak incidence in the 7–8th decades of life. However, VSCCs can also occur in young women. This unfortunate event is even rarer and more worrisome in pregnant women, being hard to manage for gynecologists, oncologists, and radiotherapists. Very few cases have been reported and we felt the need for an updated review on this topic. Thus, we performed a systematic literature review of VSCCs diagnosed during pregnancy, discussing the clinic-pathologic features, the implications in pregnancy outcomes, and the effects of such a diagnosis in the management of mothers and their babies. Abstract According to our systematic literature review (PRISMA guidelines), only 37 vulvar squamous cell carcinomas (VSCCs) were diagnosed during pregnancy (age range: 17–41 years). The tumor size range was 0.3–15 cm. The treatment was performed after (14/37, 38%), before (10/37, 27%), or before-and-after delivery (11/37, 30%). We found that 21/37 (57%) cases were stage I, 2 II (5%), 11 III (30%), and 3 IVB (8%). HPV-related features (condylomas/warts; HPV infection; high-grade squamous intraepithelial lesion) were reported in 11/37 (30%) cases. We also found that 9/37 (24%) patients had inflammatory conditions (lichen sclerosus/planus, psoriasis, chronic dermatitis). The time-to-recurrence/progression (12/37, 32%) ranged from 0 to 36 (mean 9) months. Eight women died of disease (22%) 2.5–48 months after diagnosis, 2 (5%) were alive with disease, and 23 (62%) were disease-free at the end of follow-up. Pregnant patients must be followed-up. Even if they are small, newly arising vulvar lesions should be biopsied, especially in women with risk factors (HPV, dermatosis, etc.). The treatment of VSCCs diagnosed in late third trimester might be delayed until postpartum. Elective cesarean section may prevent vulvar wound dehiscence. In the few reported cases, pregnancy/fetal outcomes seemed to not be affected by invasive treatments during pregnancy. However, clinicians must be careful; larger cohorts should define the best treatment. Definite guidelines are lacking, so a multidisciplinary approach and discussion with patients are mandatory.

Genomically actionable mutations are increasingly used to deliver personalized medical care for patients with ovarian cancer (OC). Liquid biopsy applications encompass the identification and study of circulating tumor DNA (ctDNA), cell-free DNA, circulating tumor cells, and sometimes circulating miRNAs. In the current practice, ctDNA is mostly utilized. The multiple clinical applications of liquid biopsy in oncology have facilitated the implementation of precision medicine in practice. Though not still ready for clinical use in OC daily practice, the use of liquid biopsy in the experimental setting has revolutionized the study of the mechanisms of carcinogenesis and treatment resistance underlying the clinical disease progression. Moreover, as a minimally invasive approach, liquid biopsy can be used to predict response to antineoplastic therapies, including standard platinum-based chemotherapy regimens and PARP inhibitors. In addition, liquid biopsy can also be used in OC to predict recurrence, inform on the prognosis and anticipate clinical progression-free survival events. In this chapter, the clinical relevance and utility of blood-based ctDNA in OC are reviewed.

We assessed the predictive accuracy of the Warfarin Pharmacogenetics Consortium (IWPC) algorithm in a prospective cohort of 376 high-risk elderly patients (≥65 years) who required new treatment with warfarin for either medical (non valvular atrial fibrillation) or surgical conditions (heart valve replacement), had ≥1 comorbid conditions, and regularly used ≥2 other drugs. Follow-up visits were performed according to clinical practice and lasted for a maximum of 1 year. Two hundred and eighty-three (75%) patients achieved a stable maintenance dose. Warfarin maintenance doses were low on average (median 20.3 mg/week, interquartile range, 14.1–27.7 mg/week) and were substantially overestimated by the IWPC algorithm. Overall the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable dose was equal to 37.5%, (95% CI 32.0–43.3%). IWPC algorithm explained only 31% of the actual warfarin dose variability. Modifications of the IWPC algorithm are needed in high-risk elderly people.