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Pembrolizumab, an anti-PD-1 antibody, has been approved as first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma ((R/M) HNSCC). However, only a minority of patients benefit from immunotherapy, which highlights the need to identify novel biomarkers to optimize treatment strategies. CD137+ T cells have been identified as tumour-specific T cells correlated with immunotherapy responses in several solid tumours. In this study, we investigated the role of circulating CD137+ T cells in (R/M) HNSCC patients undergoing pembrolizumab treatment. PBMCs obtained from 40 (R/M) HNSCC patients with a PD-L1 combined positive score (CPS) ≥1 were analysed at baseline via cytofluorimetry for the expression of CD137, and it was found that the percentage of CD3+CD137+ cells is correlated with the clinical benefit rate (CBR), PFS, and OS. The results show that levels of circulating CD137+ T cells are significantly higher in responder patients than in non-responders (p = 0.03). Moreover, patients with CD3+CD137+ percentage ≥1.65% had prolonged OS (p = 0.02) and PFS (p = 0.02). Multivariate analysis, on a combination of biological and clinical parameters, showed that high levels of CD3+CD137+ cells (≥1.65%) and performance status (PS) = 0 are independent prognostic factors of PFS (CD137+ T cells, p = 0.007; PS, p = 0.002) and OS (CD137+ T cells, p = 0.006; PS, p = 0.001). Our results suggest that levels of circulating CD137+ T cells could serve as biomarkers for predicting the response of (R/M) HNSCC patients to pembrolizumab treatment, thus contributing to the success of anti-cancer treatment.

Supplementary Table from Circulating CD137+ T Cells Correlate with Improved Response to Anti-PD1 Immunotherapy in Patients with Cancer

Supplementary Figure from Circulating CD137+ T Cells Correlate with Improved Response to Anti-PD1 Immunotherapy in Patients with Cancer

Purpose:CD137 molecule is expressed by activated lymphocytes, and in patients with cancer identifies the tumor-reactive T cells. In solid tumors, high levels of circulating CD137+ T cells are associated with the clinical response and the disease-free status. Here, we examined the role of the CD137+ T cells in the improvement of patients' selection for immunotherapy treatment.Experimental Design:Peripheral blood mononuclear cells derived from 109 patients with metastatic cancer (66 patients for the identification cohort and 43 for the validation cohort) were analyzed for the expression of CD3, CD4, CD8, CD137, and PD1 molecules before the beginning of anti-PD1 therapy. Twenty healthy donors were used as control. The soluble form of CD137 (sCD137) was also analyzed. The CD137+ T cell subsets and the sCD137 were correlated with the clinicopathologic characteristics. The distribution of CD137+ T cells was also examined in different tumor settings.Results:The percentage of CD137+ T cells was higher in healthy donors and in those patients with a better clinical status (performance status = 0–1, n°metastasis≤2) and these high levels were ascribed to the CD8+CD137+ T cell population. The high frequency of CD137+ and CD8+CD137+ T cells resulted as a prognostic factor of overall survival (OS) and progression-free survival (PFS), respectively, and were confirmed in the validation cohort. High levels of CD3+CD137+PD1+ lymphocytes were associated with a low number of metastasis and longer survival. Instead, the high concentration of the immunosuppressive sCD137 in the serum is associated with a lower PFS and OS. In tumor bed, patients with a complete response showed a high percentage of CD137+ and CD8+ T cells.Conclusions:We propose the CD137+ T subset as an immune biomarker to define the wellness status of the immune system for successful anticancer immunotherapy.

Purpose: CD137 molecule is expressed by activated lymphocytes, and in patients with cancer identifies the tumor-reactive T cells. In solid tumors, high levels of circulating CD137+ T cells are associated with the clinical response and the disease-free status. Here, we examined the role of the CD137+ T cells in the improvement of patients' selection for immunotherapy treatment. Experimental Design: Peripheral blood mononuclear cells derived from 109 patients with metastatic cancer (66 patients for the identification cohort and 43 for the validation cohort) were analyzed for the expression of CD3, CD4, CD8, CD137, and PD1 molecules before the beginning of anti-PD1 therapy. Twenty healthy donors were used as control. The soluble form of CD137 (sCD137) was also analyzed. The CD137+ T cell subsets and the sCD137 were correlated with the clinicopathologic characteristics. The distribution of CD137+ T cells was also examined in different tumor settings. Results: The percentage of CD137+ T cells was higher in healthy donors and in those patients with a better clinical status (performance status = 0–1, n°metastasis≤2) and these high levels were ascribed to the CD8+CD137+ T cell population. The high frequency of CD137+ and CD8+CD137+ T cells resulted as a prognostic factor of overall survival (OS) and progression-free survival (PFS), respectively, and were confirmed in the validation cohort. High levels of CD3+CD137+PD1+ lymphocytes were associated with a low number of metastasis and longer survival. Instead, the high concentration of the immunosuppressive sCD137 in the serum is associated with a lower PFS and OS. In tumor bed, patients with a complete response showed a high percentage of CD137+ and CD8+ T cells. Conclusions: We propose the CD137+ T subset as an immune biomarker to define the wellness status of the immune system for successful anticancer immunotherapy.

ObjectiveEndometrial carcinoma is the most common gynecological tumor in developed countries. Clinicopathological factors and molecular subtypes are used to stratify the risk of recurrence and to tailor adjuvant treatment. The present study aimed to assess the role of radiomics analysis in pre-operatively predicting molecular or clinicopathological prognostic factors in patients with endometrial carcinoma.MethodsLiterature was searched for publications reporting radiomics analysis in assessing diagnostic performance of MRI for different outcomes. Diagnostic accuracy performance of risk prediction models was pooled using the metandi command in Stata.ResultsA search of MEDLINE (PubMed) resulted in 153 relevant articles. Fifteen articles met the inclusion criteria, for a total of 3608 patients. MRI showed pooled sensitivity and specificity 0.785 and 0.814, respectively, in predicting high-grade endometrial carcinoma, deep myometrial invasion (pooled sensitivity and specificity 0.743 and 0.816, respectively), lymphovascular space invasion (pooled sensitivity and specificity 0.656 and 0.753, respectively), and nodal metastasis (pooled sensitivity and specificity 0.831 and 0.736, respectively).ConclusionsPre-operative MRI-radiomics analyses in patients with endometrial carcinoma is a good predictor of tumor grading, deep myometrial invasion, lymphovascular space invasion, and nodal metastasis.

OBJECTIVE Spread through air spaces (STAS) is a pattern of invasion present in some adenocarcinomas (ADC). The goal of this study was to assess the impact of STAS in patients treated with different types of surgical resections and on the clinical outcome in patients with ADC of different diameters and with different degrees of nodal involvement. METHODS A total of 109 patients were reviewed. Complete surgical resection with systematic nodal dissection was achieved in all patients. The median follow-up was 65 months (3–90 months). RESULTS STAS was observed in 70 cases (64.2%); 13 patients (18.5%) had lymph node involvement (N1 and N2). Overall survival and progression-free survival were higher in patients without STAS (P = 0.042; P = 0.027). The presence of STAS in tumours ≤2 cm was a predictor of worse progression-free survival following sublobar resection compared to major resections (P = 0.011). Sublobar resection of N0 STAS-positive tumours was associated with worse long-term survival compared to a major resection (P = 0.04). Statistical analyses showed that age >70 years and recurrence were independent variables for survival; smoking pack-years >20, sublobar resection and nodal involvement were independent variables for recurrence; and smoking pack-years >20 were independent variables for a history of cancer and pleural invasion for local recurrence. CONCLUSIONS STAS seems to play a role in long-term survival, particularly for patients with N0 and tumours smaller than 2 cm. Further studies are necessary to validate this hypothesis.

BACKGROUND/AIM Although still controversial, the current treatment for locally advanced neuroendocrine carcinoma of the cervix (NECC) relies on chemoradiation (CRT). The aim of this study is to evaluate the alternative role of combined chemotherapy and surgery in treating NECC. PATIENTS AND METHODS This is a retrospective series of patients undergoing radical surgery after neoadjuvant chemotherapy (NACT) for locally advanced NECC (stages IIB-IVA). Histological examination and immunohistochemistry were performed on surgical specimens to confirm diagnosis. Systematic literature search was conducted to identify other cases treated with chemotherapy and surgery. RESULTS Seven patients with a mean age of 49 years were identified. The mean greatest diameter at diagnosis was 59.3±24.7 mm. FIGO stage was IIB in 14.3% of patients, IIIB in 28.6%, IIIC in 42.9%, and IVA in 14.3%. The response to NACT was partial, ranging from 50% to 80%. Neuroendocrine markers were expressed in all cases. The mean progression-free survival (PFS) and overall survival (OS) were 15.0±30.6 months and 26.3±36.4 months, respectively. Eleven studies encompassing a total of 27 patients met eligibility criteria for the systematic review. CONCLUSION Surgery after NACT for locally advanced NECC may yield similar outcomes compared to CRT. The benefit of performing surgery as a primary approach could lie in the possibility of reserving CRT for recurrences. Since randomized clinical trials are difficult to be designed, an expert consensus is required to address the non-inferiority of radical surgery over CRT.

Background Metastasis is the main cause of breast cancer (BC) mortality. Increasing evidence points to a role of syndecan-1 (CD138) expression as a prognostic marker involved in BC tissue and leptomeningeal metastasis. Aim of this study was to investigate and compare syndecan-1 tissue expression and localization in primary and secondary BC, focusing on brain metastases. Methods Syndecan-1 expression was determined by immunohistochemistry. Focal vs diffuse ( 50% of cancer cells, respectively) pattern of expression, cellular localization (cytoplasm vs membrane) and intensity of immunostaining on neoplastic cells were evaluated. Moreover, the extent and pattern of expression of syndecan-1 were compared between primary tumors and paired metastases and correlated with the tumor intrinsic subtype. Results A total of 23 cases, 10 with paired primary and metastatic tumor and 13 brain metastases, were evaluated. Syndecan-1 was expressed in both primary and metastatic BC. A diffuse cytoplasmic expression was observed in most primary BCs; by contrast, all metastatic lesions showed a membrane pattern of expression, suggesting a shift in cellular localization of syndecan-1 during the metastatic process. Concerning the extent of expression, we observed in metastatic lesions, a trend of association between intrinsic subtypes and extent of positivity. In particular, both BC characterized by overexpression of HER2 and triple-negative tumors were correlated with a diffuse pattern of expression with a moderate to strong intensity. Conclusion A diffuse cytoplasmic expression was observed in most primary BCs; by contrast, all metastatic lesions showed a membrane pattern of expression, suggesting a shift in cellular localization of syndecan-1 during the metastatic process.

Coronary microvascular dysfunction (CMD) is a key pathophysiological feature of hypertrophic cardiomyopathy (HCM), contributing to myocardial ischemia and representing a critical determinant of patients' adverse outcome. The molecular mechanisms underlying the morphological and functional changes of CMD are still unknown. Aim of this study was to obtain insights on the molecular pathways associated with microvessel remodeling in HCM.Interventricular septum myectomies from patients with obstructive HCM (n = 20) and donors' hearts (CTRL, discarded for technical reasons, n = 7) were collected. Remodeled intramyocardial arterioles and cardiomyocytes were microdissected by laser capture and next-generation sequencing was used to delineate the transcriptome profile.We identified 720 exclusive differentially expressed genes (DEGs) in cardiomyocytes and 1315 exclusive DEGs in remodeled arterioles of HCM. Performing gene ontology and pathway enrichment analyses, we identified selectively altered pathways between remodeled arterioles and cardiomyocytes in HCM patients and controls.We demonstrate the existence of distinctive pathways between remodeled arterioles and cardiomyocytes in HCM patients and controls at the transcriptome level.

Summary Atypical cellular neurothekeoma (ACN) is an aggressive and rare variant of cellular neurothekeoma. Only few cases have been reported in the literature and the biological behavior seems to be uncertain. We describe the case of an ACN presenting on the scalp of an elderly man, emphasizing the cytologic features of malignancy. In addition, we provide a brief overview of the literature and discuss the differential diagnosis with other entities, and the possible diagnostic pitfalls.

Background: Xanthomas are well-circumscribed benign proliferative lesions seen mainly in soft tissues. Usually, they are found in hyperlipidemia and hyperlipoproteinemia family. Histologically, are characterized by macrophage-like mononuclear cells, multinucleated giant cells and abundant foam cells. The bone involvement, however, is notoriously rare and rib localization is extremely rare. Case presentation: A 55-year-old man performed a chest X-Ray and a subsequent chest Computed Tomography (CT) scan showing a rib lesion that was surgically removed and a diagnosis of rib xanthoma was made. The patient presented an unknown condition of hyperlipidemia. Conclusion: Rib xanthoma can be discovered accidentally and can be helpful in identifying an unrecognized condition of hyperlipidemia.

Background: Immunotherapy has revolutionized the approach to metastatic triple-negative breast cancers (mTNBC). Atezolizumab was approved for patients with mTNBC whose tumours express PD-L1, determined by SP 142 assay. To assess the availability and practice of SP142 test we administered a survey to all the 15 Pathology Departments of the Lazio Region during a 6-months period.Methods: The survey comprised 12 questions regarding the availability of SP142 in the Pathology Departments, the percentage of positive tests, the difficulties of pathologists in case close to cut-off value and the tested samples.Results: The SP142 assay was available only in 8 Centers. In case of positive result, most Centers (5/8, 62.5%) reported values of PD-L1 expression ranging from > 1 to Conclusion: Our results raise some important issues concerning the evaluation of PD-L1 in the “real-life” setting, providing strategies for its implementation.

Cancer immunotherapy has significantly improved the management of many malignancies in recent years. Although cervical cancer is the second most common women's cancer in the world, there are still few information about the role of checkpoint inhibitors in this neoplasm, especially in the neoadjuvant setting. In the present study, we retrieved 38 consecutive patients with squamous cell cervical cancer who underwent platinum-based neoadjuvant chemotherapy (NACT) followed by radical surgery. Pre-therapy biopsies were evaluated for the presence of tumor-infiltrating lymphocytes (TILs), including T (both cytotoxic CD8+ and helper CD4+) and B lymphocytes, macrophages, natural-killer cells, and eosinophils. Immunohistochemistry was performed to characterize the inflammatory cells and to evaluate programmed death-ligand 1 (PD-L1) expression on both neoplastic and inflammatory cells. We divided our study population in three groups using three cut-offs (10%, 10-40%,40%), for both TILs and PD-L1 evaluation. Pathological response to NACT was obtained from the histological reports of the post-therapy surgical specimens. We observed that all cases showed stromal TILs, with a predominance of CD3+/CD4+ T helper cells, thus supporting the strong immunogenic potential of cervical cancer. The vast majority of neoplasms expressed PD-L1: 100% on immune cells and 92% on tumor cells. Firstly, we noticed that the percentage of neoplastic cells PD-L1+ was positively associated with high TIL percentage (p = 0.0073) and with increased PD-L1 expression on inflammatory cells (p = 0.0297). Secondly, we observed a significant correlation between both the percentage (p = 0.0105) of TILs and the expression of PD-L1 (p = 0.01045) on inflammatory cells and pathological response to NACT. These results suggest that cervical cancer could be a good target for immunotherapy, also in the neoadjuvant setting. Furthermore, PD-L1 expression was significantly associated with stromal TILs that interestingly may predict pathological response to NACT.

Introduction: Primary sarcoma of the vulva is an extremely rare entity, representing only 1%–3% of all vulvar malignant neoplasms. Among sarcomas, leiomyosarcoma (LMS) is the most prevalent histologic variant. Due to the rarity of LMS, guidelines are lacking and phase III trials have not been carried out, so clinical management is based on local clinical practice and physician experience. Case presentation: Here, we described a case of primary LMS of the vulva and its successful management, with the adoption of neoadjuvant chemotherapy and surgery. We report a case of a 74-year-old woman with 12.5 cm vulvar LMS. The patient received three cycles of neoadjuvant chemotherapy with a partial response. Radical vulvectomy with vulvar reconstruction with V-F flap was carried out. Surgical margins were negative. Three additional cycles of adjuvant chemotherapy were delivered. Results: One year after treatment, the patient was disease-free. Conclusion: There are no approved therapeutic protocols for this rare neoplasia. Surgery is the mainstay of treatment. However, it is not always feasible, so neoadjuvant chemotherapy was delivered for downstaging the vulvar lesion. We suppose that neoadjuvant chemotherapy has optimized the possibilities of radical surgery. Despite the anectodical nature of this case presentation, neoadjuvant chemotherapy seems a valid therapeutic option for managing patients with bulky vulvar sarcoma. Further large collaborative studies are warranted to identify the best therapeutic option for these patients.

The aim of this study was to determine whether quantitative parameters obtained from intravoxel incoherent motion (IVIM) model at baseline magnetic resonance imaging (MRI) correlate with histological parameters and response to neoadjuvant chemotherapy in patients with locally advanced cervical cancer (LACC). Methods: Twenty patients with biopsy-proven cervical cancer, staged as LACC on baseline MRI and addressed for neoadjuvant chemotherapy were enrolled. At treatment completion, tumor response was assessed with a follow-up MRI evaluated using the revised response evaluation criteria in solid tumors (RECIST; version 1.1), and patients were considered good responders (GR) if they had complete response or partial remission, and poor responders/non-responders (PR/NR) if they had stable or progressive disease. MRI protocol included conventional diffusion-weighted imaging (DWI; b = 0 and 1000 s/mm2) and IVIM acquisition using eight b-values (range: 0–1500 s/mm2). MR-images were analyzed using a dedicated software to obtain quantitative parameters: diffusion (D), pseudo-diffusion (D*), and perfusion fraction (fp) from the IVIM model; apparent diffusion coefficient (ADC) from conventional DWI. Histologic subtype, grading, and tumor-infiltrating lymphocytes (TILs) were assessed in each LACC. Results: D showed significantly higher values in GR patients (p = 0.001) and in moderate/high TILs (p = 0.018). Fp showed significantly higher values in squamous cell tumors (p = 0.006). Conclusions: D extracted from the IVIM model could represent a promising tool to identify tumor aggressiveness and predict response to therapy.

BACKGROUND: Spread through air spaces (STAS) has been reported as a negative prognostic factor in patients with lung cancer undergoing sublobar resection. Radiomics has been recently proposed to predict STAS using preoperative computed tomography (CT). However, limitations of previous studies included the strict selection of imaging acquisition protocols, leading to results hardly applicable to daily clinical practice. The aim of this study is to test a radiomics-based prediction model of STAS in a practice-based dataset. METHODS: A training cohort of 99 consecutive patients (65 STAS+ and 34 STAS−) with resected lung adenocarcinoma (ADC) was retrospectively collected. Preoperative CT images were collected from different centers regardless model and scanner manufacture, acquisition and reconstruction protocol, contrast phase and pixel size. Radiomics features were selected according to separation power and P value stability within different preprocessing setups and bootstrapping resampling. A prospective cohort of 50 patients (33 STAS+ and 17 STAS−) was enrolled for the external validation. RESULTS: Only the five features with the highest stability were considered for the prediction model building. Radiomics, radiological and mixed radiomics-radiological prediction models were created, showing an accuracy of 0.66±0.02 after internal validation and reaching an accuracy of 0.78 in the external validation. CONCLUSIONS: Radiomics-based prediction models of STAS may be useful to properly plan surgical treatment and avoid oncological ineffective sublobar resections. This study supports a possible application of radiomics-based models on data with high variance in acquisition, reconstruction and preprocessing, opening a new chance for the use of radiomics in the prediction of STAS. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04893200.

High- and low-risk endometrial carcinoma (EC) differ in whether or not a lymphadenectomy is performed. We aimed to develop MRI-based radio-genomic models able to preoperatively assess lymph-vascular space invasion (LVSI) and discriminate between low- and high-risk EC according to the ESMO-ESGO-ESTRO 2020 guidelines, which include molecular risk classification proposed by “ProMisE”. This is a retrospective, multicentric study that included 64 women with EC who underwent 3T-MRI before a hysterectomy. Radiomics features were extracted from T2WI images and apparent diffusion coefficient maps (ADC) after manual segmentation of the gross tumor volume. We constructed a multiple logistic regression approach from the most relevant radiomic features to distinguish between low- and high-risk classes under the ESMO-ESGO-ESTRO 2020 guidelines. A similar approach was taken to assess LVSI. Model diagnostic performance was assessed via ROC curves, accuracy, sensitivity and specificity on training and test sets. The LVSI predictive model used a single feature from ADC as a predictor; the risk class model used two features as predictors from both ADC and T2WI. The low-risk predictive model showed an AUC of 0.74 with an accuracy, sensitivity, and specificity of 0.74, 0.76, 0.94; the LVSI model showed an AUC of 0.59 with an accuracy, sensitivity, and specificity of 0.60, 0.50, 0.61. MRI-based radio-genomic models are useful for preoperative EC risk stratification and may facilitate therapeutic management.

Well-differentiated lung neuroendocrine tumours (Lu-NETs), classified as typical (TC) and atypical (AC) carcinoids, represent 30% of NETs. Angiogenesis plays an essential role in NET development and progression. A higher vascular network is a marker of differentiation, with positive prognostic implications. Materials and Methods: We retrospectively evaluated microvessel density (MVD) by CD34 immunohistochemical (IHC) staining and hypoxia by IHC staining for Hypoxia-inducible factor 1α (HIF-1α), comparing right- and left-lung parenchyma in 53 lung NETs. Results: The median age was 66 years (39–81), 56.6% males, 24.5% AC, 40.5% left-sided tumours and 69.8% TNM stage I. The mitotic count was

Objectives: To investigate the role of quantitative Magnetic Resonance Imaging (MRI) in preoperative assessment of tumour aggressiveness in patients with endometrial cancer, correlating multiple parameters obtained from diffusion and dynamic contrast-enhanced (DCE) MR sequences with conventional histopathological prognostic factors and inflammatory tumour infiltrate. Methods: Forty-four patients with biopsy-proven endometrial cancer underwent preoperative MR imaging at 3T scanner, including DCE imaging, diffusion-weighted imaging (DWI) and intravoxel incoherent motion imaging (IVIM). Images were analysed on dedicated post-processing workstations and quantitative parameters were extracted: Ktrans, Kep, Ve and AUC from the DCE; ADC from DWI; diffusion D, pseudo diffusion D*, perfusion fraction f from IVIM and tumour volume from DWI. The following histopathological data were obtained after surgery: histological type, grading (G), lympho-vascular invasion (LVI), lymph node status, FIGO stage and inflammatory infiltrate. Results: ADC was significantly higher in endometrioid histology, G1-G2 (low grade), and stage IA. Significantly higher D* were found in endometrioid subptype, negative lymph nodes and stage IA. The absence of LVI is associated with higher f values. Ktrans and Ve values were significantly higher in low grade. Higher D*, f and AUC occur with the presence of chronic inflammatory cells, D * was also able to distinguish chronic from mixed type of inflammation. Larger volume was significantly correlated with the presence of mixed-type inflammation, LVI, positive lymph nodes and stage ≥IB. Conclusions: Quantitative biomarkers obtained from pre-operative DWI, IVIM and DCE-MR examination are an in vivo representation of the physiological and microstructural characteristics of endometrial carcinoma allowing to obtain the fundamental parameters for stratification into Risk Classes. Advances in knowledge: Quantitative imaging biomarkers obtained from DWI, DCE and IVIM may improve preoperative prognostic stratification in patients with endometrial cancer leading to a more informed therapeutic choice.

This abstract was not presented at the conference. Citation Format: Botticelli A, Cerbelli B, Pisano A, Naso G, Monti M, Ascierto PA, Costarelli L, Magri V, Mauri M, Pignataro MG, Campagna D, Pernazza A, Nuti M, Fortunato L, Della Rocca C, D'Amati G, Marchetti P. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-12-08.

Ciliated epithelial cells have been rarely observed in urothelium lined mucosa. Only extremely rare reports in the literature have described this phenomenon and no cases have been described in other sites than the male urethra. Herein, we illustrate the finding of ciliated pseudostratified columnar cells in the renal calyx mucosa adjacent to an area of urothelial invasive carcinoma in an 82 year-old man with previous history of nephrolithiasis. The ciliated cells covered a linear extension of 0.5 cm: they were positive for keratin 7 and keratin 8/18 and negative for keratin 20. Alcian blue staining was positive in some vacuoles in the apical cytoplasm of the same cells whereas PAS (Periodic Acid-Schiff) staining was negative. GATA3 resulted negative in ciliated cells except for a layer in the basal portion of the epithelium, just above the basal membrane. The actual prevalence of ciliated epithelia in the urinary tract is not well documented and the current knowledge on the subject is limited to electron scanning microscopy studies. The significance of this phenomenon remains unknown: it could be either a developmental abnormality or more probably a metaplastic change. Associated urolithiasis, which has been described in both a previous report and in the present one, could hypothetically represent a possible trigger for this unusual cell change. However, this hypothesis needs to be confirmed through further investigation.

Background/aim Treatment of locally advanced cervical cancer (LACC) consists of concomitant chemoradiation or neoadjuvant chemotherapy (NACT) plus radical surgery (RS). This study analyzed the prognostic role of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), tumor infiltrating lymphocytes (TILs), and PD-L1 expression in LACC patients, treated with NACT+RS. Patients and methods We prospectively analyzed 37 LACC patients treated from December 2016 to September 2019. Patients were submitted to pelvic examination, biopsy and imaging. Results In 65% of cases, a nodal involvement was present at pre-treatment MRI. All cancers showed the presence of stromal TILs and PD-L1 staining of inflammatory cells. No significant correlations were found between clinicopathological parameters and the number of TILs and PDL-1 at baseline. After NACT, 29 patients (78%) were submitted to RS; 28% of patients showed pathological complete response, 62% partial response and 10% stable disease. Seven (24%) patients reported a positive node. Patients with high levels of stromal TILs and low NLR and PLR showed a significantly better response to NACT. No significant correlation was observed between PD-L1 expression and response to NACT. Conclusion The number of TILs, the expression of PDL1, and NLR and PLR ratios correlate significantly with the response of LACC patients to NACT.

Background Slow progression and good prognosis are the usual characteristics of papillary thyroid carcinoma (PTC). The presence of brain metastases (0.4–1.2%) is suggestive of a worse prognosis. RET/PTC rearrangements were particularly prevalent in PTCs developed after Chernobyl nuclear accident. Case description A 50-year-old woman born in Slovakia, exposed to radiation resulting from the accident at the Chernobyl nuclear power plant, affected since 2017 by papillary thyroid cancer and in therapy at our hospital, experimented cerebral hemorrhagic metastasis. Biopsy analyses revealed a RET/PTC3 rearrangement, so our aim was to find possible morphological relation between hemorrhagic metastasis and RET/PTC3 translocation. Results Immunohistochemical analysis showed diffuse and intense positivity for VEGF in endothelial cells of the neoplasm’ vascular network. Transmission electron microscopy images showed vessels with unorganized pattern and uneven diameters. In particular, metastasis endothelial cells (MECs) showed irregular shape and size, thickened cytoplasm and swelling of endoplasmic reticulum. MECs organized in irregular monolayers or multiple layers, surrounded by a thickened but unstructured extracellular matrix. Absence of strong junctional complexes among MECs resulted in a further weakened vessels wall. Conclusion RET/PTC3 translocation causes VEGF overexpression via STAT3 signaling cascade and the increased amount of VEGF adds to the greater amount of VEGFRs expressed by MECs. Our ultrastructural investigation show that this condition creates a massive growth of altered vessels prone to bleeding. The clinical significance of our study consists in alert oncologist and surgeons on possible arising of hemorrhagic brain metastases in patients with PTC and RET/PTC3 translocation exposed to ionizing radiation as people living in areas caught up in Chernobyl or Fukushima disasters.

Purpose The assessment of Programmed death-ligand 1 (PD-L1) expression has become a game changer in the treatment of patients with advanced non-small cell lung cancer (NSCLC). We aimed to investigate the ability of Radiomics applied to computed tomography (CT) in predicting PD-L1 expression in patients with advanced NSCLC. Methods By applying texture analysis, we retrospectively analyzed 72 patients with advanced NSCLC. The datasets were randomly split into a training cohort (2/3) and a validation cohort (1/3). Forty radiomic features were extracted by manually drawing tumor volumes of interest (VOIs) on baseline contrast-enhanced CT. After selecting features on the training cohort, two predictive models were created using binary logistic regression, one for PD-L1 values ≥ 50% and the other for values between 1 and 49%. The two models were analyzed with ROC curves and tested in the validation cohort. Results The Radiomic Score (Rad-Score) for PD-L1 values ≥ 50%, which consisted of Skewness and Low Gray-Level Zone Emphasis (GLZLM_LGZE), presented a cut-off value of − 0.745 with an area under the curve (AUC) of 0.811 and 0.789 in the training and validation cohort, respectively. The Rad-Score for PD-L1 values between 1 and 49% consisted of Sphericity, Skewness, Conv_Q3 and Gray Level Non-Uniformity (GLZLM_GLNU), showing a cut-off value of 0.111 with AUC of 0.763 and 0.806 in the two population, respectively. Conclusion Rad-Scores obtained from CT texture analysis could be useful for predicting PD-L1 expression and guiding the therapeutic choice in patients with advanced NSCLC.

Purpose The distinction between multiple primary lung cancers (MPLCs) and intrapulmonary metastases has a significant impact on tumor staging and therapeutic choices. Several criteria have been proposed to solve this diagnostic issue, but a definitive consensus is still missing. We tested the efficacy of a combined clinical, histopathological and molecular (“real world”) approach for the correct classification of multiple lung tumors in a selected cohort of patients. Methods 24 multiple lung tumors with a diagnosis of adenocarcinoma from 10 patients were retrospectively reviewed. Radiological, pathological and clinical information, including follow-up, were integrated with molecular profiling via a routine multigene panel sequencing. Results Comprehensive histologic assessment revealed readily distinguishable histologic patterns between multiple tumors suggesting unrelated lesions in 7 cases, in agreement with clinical, radiological and molecular data, thus leading to final diagnosis of MPLCs. In the remaining 3 cases, the differential diagnosis between MPLCs and intrapulmonary metastases was challenging, since the histologic features of the lesions were similar or identical. The final interpretation (2 MPLCs and 1 most likely intrapulmonary metastases) was reached thanks to the integration of all available data, and was confirmed by follow-up. Conclusions A multidisciplinary approach including a routinely affordable multigene panel sequencing is a useful tool to discriminate MPLCs from intrapulmonary metastases in multiple lung nodules sharing the adenocarcinoma histotype.

Pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) can predict better survival outcomes in patients with early triple negative breast cancer (TNBC). Tumor infiltrating lymphocytes (TILs), Programmed Death-Ligand 1 (PD-L1), and Cluster of Differentiation 73 (CD73) are immune-related biomarkers that can be evaluated in the tumor microenvironment. We investigated if the contemporary expression of these biomarkers combined in a tissue immune profile (TIP) can predict pCR better than single biomarkers in TNBC. Tumor infiltrating lymphocytes (TILs), CD73 expression by cancer cells (CC), and PD-L1 expression by immune cells (IC) were evaluated on pre-NACT biopsies. We defined TIP positive (TIP+) as the simultaneous presence of TILS &ge, 50%, PD-L1 &ge, 1%, and CD73 &le, 40%. To consider the effects of all significant variables on the pCR, multivariate analysis was performed. Akaike information criterion (AIC) and Bayesian information criterion (BIC) were used for model selection. We retrospectively analyzed 60 biopsies from patients with TNBC who received standard NACT. Pathological complete response was achieved in 23 patients (38.0%). Twelve (20.0%) cases resulted to be TIP+. The pCR rate was significantly different between TIP+ (91.7%) and TIP&minus, (25.0%) (p &lt, 0.0001). Using a multivariate analysis, TIP was confirmed as an independent predictive factor of pCR (OR 49.7 (6.30&ndash, 392.4), p &lt, 0.0001). Finally, we compared the efficacy of TIP versus each single biomarker in predicting pCR by AIC and BIC. The combined immune profile is more accurate in predicting pCR (AIC 68.3, BIC 74.5) as compared to single biomarkers. The association between TIP+ and pCR can be proposed as a novel link between immune background and response to chemotherapy in TNBC, highlighting the need to consider an immunological patients&rsquo, profile rather than single biomarkers.

Despite the current pandemic season, reports on pathologic features of Coronavirus disease 19 (COVID-19) are exceedingly rare at the present time. Here we describe the pathologic features of early lung involvement by COVID-19 in a surgical sample resected for carcinoma from a patient who developed SARS-CoV-2 infection soon after surgery. The main histologic findings observed were pneumocyte damage, alveolar hemorrhages with clustering of macrophages, prominent and diffuse neutrophilic margination within septal vessels and interstitial inflammatory infiltrates, mainly represented by CD8+ T lymphocytes. These features are similar to those previously described in SARS-CoV infection. Subtle histologic changes suggestive pulmonary involvement by Covid-19 may be accidentally encountered in routine pathology practice, especially when extensive sampling is performed for histology. These findings should be carefully interpreted in light of the clinical context of the patient and could prompt a pharyngeal swab PCR test to rule out the possibility of SARS-CoV-2 infection in asymptomatic patients.

Background Despite the incidence of Frontal fibrosing alopecia (FFA) has been increasing in last two decades, the pathophysiology and trigger factors of FFA have not been yet fully understood. Aims The aim of this study was to describe epidemiology, clinical and trichoscopic features and comorbidities of FFA patients, in order to improve the understanding of this disease. Patients/methods A retrospective, observational monocentric study was conducted from 2003 to 2019. Data concerning epidemiology (age, gender, age of menopause, and age of FFA onset), comorbidities, current therapies, localization of FFA (such as frontotemporal hairline, occipital, eyebrow, eyelash, beard, sideburns, and body hair), presence of papules and sign of Lichen planus (LP) at skin, mucosae and/or nail were collected for each patient included. Results A total of 119 Caucasian, adult patients (8 men and 111 female) with FFA were enrolled in the study. Cutaneous, mucosal, or nail localization of LP were found in 16% of our subjects. Interestingly, 15 out of 119 subjects (10.61%) were affected by concomitant genital Lichen sclerosus (LS) and 5 out of these 15 patients (4.38%) presented both LS and LP in association with FFA. Conclusion Considering the high prevalence of LS in FFA patients in our case series, and the frequency of autoimmune comorbidities in both LS and FFA, it is possible to hypothesize an autoimmune process in both conditions. Further studies are needed for a better understanding of the nature of the association between LS and FFA.

The immune system plays a key role in tumor surveillance and escape. Recently, CD73 has been proposed as a prognostic biomarker associated with disease-free survival and overall survival in triple negative breast cancer (TNBC). In this study, we investigated the role of both CD73 expression and stromal tumor–infiltrating lymphocytes (TILs) in predicting the pathologic response of TNBC to neoadjuvant chemotherapy (NACT). We retrospectively analyzed CD73 immunohistochemical expression and stromal TILs on 61 consecutive biopsies from patients who received standard NACT. Twenty-three patients (38%) achieved pathologic complete response (pCR). TILs were present in the majority of biopsies (93%) with percentages ranging from 2 to 80%. High TILs (≥ 50%) were found in 30% of cases, and in this group, pCR was achieved in 76.5% of cases. Levels of TILs were associated with a better pathologic response only at univariate analysis (p = 0.037). The median value of CD73 expression on tumor cells was 40%. In 32 (52.5%) basal biopsies, CD73 expression was below or equal to median value (“low CD73”). A pCR was obtained in 53% of cases with “low CD73” and in 21% with high CD73, and this was statistically different both at univariate (p = 0.011) and multivariate (p = 0.014) analysis. Our results suggest that CD73 expression better predicts the response to NACT than TILs in TNBC. Characterization of both TILs and microenvironment could be a promising approach to personalize treatment.

Background and Aims Carcinoma cuniculatum (CC) is a rare variant of an extremely well-differentiated squamous cell carcinoma. The most commonly involved site is the skin, with a preference for the sole. Only 15 cases of esophageal CC have been reported so far. Based on published data, the clinical behavior of CC has not been clearly defined. We describe the clinical-pathologic features of two cases of esophageal CC, and provide a review of the available literature, to shed more light on this unusual tumor. Methods A detailed gross and histologic analysis was performed on two cases of surgically treated esophageal CC. The patients were followed-up after surgery. A systematic search was also done concerning studies focused on esophageal CC. A search of the electronic databases MEDLINE-PubMed was conducted using the following research terms: (esophagus) AND (cuniculatum carcinoma). Results Both patients were alive at last follow-up at six and nine months from surgery without any recurrence. Concerning the fifteen cases reported from the systematic review, median follow-up after surgery was very long as compared to common esophageal cancers (4.0 years), with only one recurrence observed. Conclusion CC shows an indolent clinical behavior, with a low recurrence rate after radical surgery. The diagnosis of this rare tumor is typically made after surgery. An aggressive approach is required with curative intents.

We describe a rare case of Dirofilaria repens infection presenting as peripheral lung nodules and mimicking a metastatic focus from a previously diagnosed cutaneous melanoma. To avoid invasive investigations before arriving at the correct diagnosis, dirofilariasis should be included as a part of the diagnostic process in subjects with lung nodules who live in (or have traveled to) endemic regions.

Sialolithiasis is a non-neoplastic salivary gland disease that rarely affects the minor salivary glands. There are no guidelines in the literature which can suggest which is the best surgical approach to treat Minor Salivary Glands Sialolithiasis (MSGL). The present case was of a 48-year-old male patient complaining of painful swelling localized in the left back-commissural zone which was 0.5 mm in diameter, for which surgical enucleation approach was done and in that some small calcific masses ranging from 0.2 to 4 mm in diameter were found. They were surrounded by granulation tissue and associated with small pus oozing. Histopathological examination was carried out leading to a final diagnosis of MSGL.

We evaluated the impact of breast cancer subtypes on pathologic complete response (pCR) in 181 patients with positive nodes undergoing neoadjuvant chemotherapy (NAC). After NAC, patients underwent surgery, with sentinel lymph node biopsy (SLNB) or axillary dissection (ALND). In 28.2% of cases a pCR was achieved, with the highest rate in Her2+ and triple negative tumors. Overall, nodal pCR was more frequent than breast pCR (P = 0.003) with higher percentages in Her2+ and LLB-Her2+ (P < 0.05). In the Her2+ group, nodal pCR was observed only with breast pCR. Thus, in Her2+ tumors, breast pCR predicts node pCR, supporting the use of SLNB in this subgroup to stage the axilla avoiding ALND.

Background Symptoms and signs of myocardial ischemia in the absence of obstructive coronary disease are common in hypertensive patients. This can be explained by coronary microvascular dysfunction (CMD) due to adverse remodeling of coronary arterioles which have also been reported in the spontaneously hypertensive rat (SHR). Objective The aim of this study was to compare the effect of Ramipril, Perindopril, Candesartan, Atenolol, Amlodipine, Indapamide and HMR1766 on coronary microvascular dysfunction (CMD) in the spontaneously hypertensive rat (SHR). Methods Eight groups of 24 week old SHR were treated for 8 weeks. Blood pressure (BP) was measured invasively at the end of treatment. After sacrifice, hearts were mounted on a Langendorff apparatus for measurement of hyperemic coronary flow (CF). Hearts were then processed for histomorphometric analysis. Results All compounds, except HMR1766, induced a significant reduction of BP. Perindopril and Candesartan increased hyperemic CF whereas the other compounds had no significant effect. Perindopril, Ramipril, Atenolol, Indapamide and HMR1766 induced significant reverse arteriolar remodeling whereas Candesartan and Amlodipine did not. Conclusions The effect of anti-hypertensive treatment on CMD is not only dependent on BP reduction. Compounds with comparable anti-hypertensive efficacy may exert different effects on CF and induce different degrees of reverse arteriolar remodeling. This article is protected by copyright. All rights reserved.

Triple negative breast cancer (TNBC) has an aggressive clinical behaviour, with a poorer prognosis compared to other subtypes. Recently, tumor-infiltrating lymphocytes (TILs) have been proposed as a predictive biomarker for a better clinical outcome and pathological response (pR) after neoadjuvant chemotherapy (NACT) in TNBC. These data confirm the role of the immune system in the neoplastic progression and in the response to therapy. We performed a retrospective analysis of 54 pre-NACT biopsies of TNBC and compared both the percentage of stromal TILs and the degree of PD-L1 expression with the extent of pR to standard NACT. A pathological complete response (pCR) was achieved in 35% of cases. Univariate analysis showed (i) a significant association between PD-L1 expression in ≥25% of neoplastic cells and the achievement of a pCR (p=0.024); (ii) a significantly higher frequency of pCR in cases showing ≥50% stromal TILs (p<0.001). However in the multivariate analysis only PD-L1 expression on tumor cells remained significantly associated with pCR (OR = 1,13; 95% CI 1,01–1,27), suggesting that the expression of this biomarker could be associated with a subpopulation of TNBC more likely to respond to chemotherapy. These data need to be confirmed by larger studies.