PAX8 Positivity, Abnormal p53 Expression, and p16 Negativity in a Primary Endometrial Squamous Cell Carcinoma: A Case Report and Review of the Literature.

Primary endometrial squamous cell carcinoma (PESCC) is a rare entity. As the clinicopathologic features and the immunophenotype have not been completely defined yet, here we report our experience and review of the literature on this topic. A 73-yr-old nulliparous woman presented with pelvic pain and vaginal bleeding. Endometrial biopsy showed a carcinoma with squamous differentiation infiltrating the myometrium. Total hysterectomy with bilateral salpingo-oophorectomy and selective pelvic lymphadenectomy was performed. Definitive diagnosis was squamous carcinoma of the endometrium, with one lymph node metastasis (stage IIIC1). Immunohistochemistry evidenced immunoreactivity of the tumor cells for cytokeratin 5, p63, cytokeratin 7, PAX8, PTEN, and cyclin D1, aberrant p53 overexpression, and Ki-67 reactivity in ~70% of the tumor cells. Estrogen and progesterone receptor, PAX2, WT1, and p16 were negative. Our case was the first PAX8-positive PESCC in the literature, underlining the Mullerian system origin of this neoplasm. Abnormal p53 expression of this case confirmed its role in the pathogenesis of PESCC. Further studies on a large number of cases are needed to better understand the pathologic features and the immunophenotype of PESCC.

Interobserver variability in the assessment of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative invasive breast carcinoma influences the association with pathological complete response: the IVITA study.

High stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC) are associated with pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Histopathological assessment of sTILs in TNBC biopsies is characterized by substantial interobserver variability, but it is unknown whether this affects its association with pCR. Here, we aimed to investigate the degree of interobserver variability in an international study, and its impact on the relationship between sTILs and pCR. Forty pathologists assessed sTILs as a percentage in digitalized biopsy slides, originating from 41 TNBC patients who were treated with NAC followed by surgery. Pathological response was quantified by the MD Anderson Residual Cancer Burden (RCB) score. Intraclass correlation coefficients (ICCs) were calculated per pathologist duo and Bland-Altman plots were constructed. The relation between sTILs and pCR or RCB class was investigated. The ICCs ranged from -0.376 to 0.947 (mean: 0.659), indicating substantial interobserver variability. Nevertheless, high sTILs scores were significantly associated with pCR for 36 participants (90%), and with RCB class for eight participants (20%). Post hoc sTILs cutoffs at 20% and 40% resulted in variable associations with pCR. The sTILs in TNBC with RCB-II and RCB-III were intermediate to those of RCB-0 and RCB-I, with lowest sTILs observed in RCB-I. However, the limited number of RCB-I cases precludes any definite conclusions due to lack of power, and this observation therefore requires further investigation. In conclusion, sTILs are a robust marker for pCR at the group level. However, if sTILs are to be used to guide the NAC scheme for individual patients, the observed interobserver variability might substantially affect the chance of obtaining a pCR. Future studies should determine the 'ideal' sTILs threshold, and attempt to fine-tune the patient selection for sTILs-based de-escalation of NAC regimens. At present, there is insufficient evidence for robust and reproducible sTILs-guided therapeutic decisions.

Shrinkage of specimens after CO2 laser cordectomy: an objective intraoperative evaluation.

PURPOSE: The margin status after CO2 laser cordectomy for glottic carcinoma may influence prognosis. There are no studies assessing the possible bias due to anatomic changes of the specimens for shrinkage. The authors evaluated the intraoperative shrinkage of specimens immediately after transoral CO2 laser microsurgery (CO2 TOLMS) to improve the understanding and the interpretation of surgical margins. METHODS: This is a prospective study involving a consecutive cohort of 23 patients (19 males, 4 females, mean age 69.9 years, range 42-83 years) with early glottic carcinoma treated by CO2 TOLMS from February 2017 to April 2019. The anteroposterior shrinkage of the specimen, of the tumor, and of the anterior and posterior margins was measured intraoperatively with a cross table reticle glass micrometer ruler, inserted into the eyepiece of the surgical microscope. RESULTS: The mean shrinkage of the mucosal specimen from intralaryngeal measurement to post-resection measurement was 3.8 ± 0.3 mm, resulting in an average loss of 29% of the anteroposterior length (p < 0.01). The anteroposterior length of both the tumor and the margins after resection significantly decreased, but the shrinkage of the anterior and posterior margins was significantly greater than the shrinkage of the tumor (49% versus 20% and 45% versus 20%, p < 0.01). CONCLUSION: The present study demonstrates significant shrinkage of specimens after CO2 TOLMS, especially in the anteroposterior length of the vocal cords, and justifies the good oncological results for specimens with close and single positive superficial margins. Follow-up versus a second surgical look policy could be safely suggested in cases of close superficial and single positive superficial margins.

Anatomical distribution and expression of CYP in humans: Neuropharmacological implications.

The cytochrome P450 (CYP450) superfamily is responsible for the metabolism of most xenobiotics and pharmacological treatments generally used in clinical settings. Genetic factors as well as environmental determinants acting through fine epigenetic mechanisms modulate the expression of CYP over the lifespan (fetal vs. infancy vs. adult phases) and in diverse organs. In addition, pathological processes might alter the expression of CYP. In this selective review, we sought to summarize the evidence on the expression of CYP focusing on three specific aspects: (a) the anatomical distribution of the expression in body districts relevant in terms of drug pharmacokinetics (liver, gut, and kidney) and pharmacodynamics, focusing for the latter on the brain, since this is the target organ of psychopharmacological agents; (b) the patterns of expression during developmental phases; and (c) the expression of CYP450 enzymes during pathological processes such as cancer. We showed that CYP isoforms show distinct patterns of expression depending on the body district and the specific developmental phases. Of particular relevance for neuropsychopharmacology is the complex regulatory mechanisms that significantly modulate the complexity of the pharmacokinetic regulation, including the concentration of specific CYP isoforms in distinct areas of the brain, where they could greatly affect local substrate and metabolite concentrations of drugs.

Zinc as a Drug for Wilson's Disease, Non-Alcoholic Liver Disease and COVID-19-Related Liver Injury.

Zinc is the second most abundant trace element in the human body, and it plays a fundamental role in human physiology, being an integral component of hundreds of enzymes and transcription factors. The discovery that zinc atoms may compete with copper for their absorption in the gastrointestinal tract let to introduce zinc in the therapy of Wilson's disease, a congenital disorder of copper metabolism characterized by a systemic copper storage. Nowadays, zinc salts are considered one of the best therapeutic approach in patients affected by Wilson's disease. On the basis of the similarities, at histological level, between Wilson's disease and non-alcoholic liver disease, zinc has been successfully introduced in the therapy of non-alcoholic liver disease, with positive effects both on insulin resistance and oxidative stress. Recently, zinc deficiency has been indicated as a possible factor responsible for the susceptibility of elderly patients to undergo infection by SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic. Here, we present the data correlating zinc deficiency with the insurgence and progression of Covid-19 with low zinc levels associated with severe disease states. Finally, the relevance of zinc supplementation in aged people at risk for SARS-CoV-2 is underlined, with the aim that the zinc-based drug, classically used in the treatment of copper overload, might be recorded as one of the tools reducing the mortality of COVID-19, particularly in elderly people.

Interobserver variability in upfront dichotomous histopathological assessment of ductal carcinoma in situ of the breast: the DCISion study.

Histopathological assessment of ductal carcinoma in situ, a nonobligate precursor of invasive breast cancer, is characterized by considerable interobserver variability. Previously, post hoc dichotomization of multicategorical variables was used to determine the "ideal" cutoffs for dichotomous assessment. The present international multicenter study evaluated interobserver variability among 39 pathologists who performed upfront dichotomous evaluation of 149 consecutive ductal carcinomas in situ. All pathologists independently assessed nuclear atypia, necrosis, solid ductal carcinoma in situ architecture, calcifications, stromal architecture, and lobular cancerization in one digital slide per lesion. Stromal inflammation was assessed semiquantitatively. Tumor-infiltrating lymphocytes were quantified as percentages and dichotomously assessed with a cutoff at 50%. Krippendorff's alpha (KA), Cohen's kappa and intraclass correlation coefficient were calculated for the appropriate variables. Lobular cancerization (KA = 0.396), nuclear atypia (KA = 0.422), and stromal architecture (KA = 0.450) showed the highest interobserver variability. Stromal inflammation (KA = 0.564), dichotomously assessed tumor-infiltrating lymphocytes (KA = 0.520), and comedonecrosis (KA = 0.539) showed slightly lower interobserver disagreement. Solid ductal carcinoma in situ architecture (KA = 0.602) and calcifications (KA = 0.676) presented with the lowest interobserver variability. Semiquantitative assessment of stromal inflammation resulted in a slightly higher interobserver concordance than upfront dichotomous tumor-infiltrating lymphocytes assessment (KA = 0.564 versus KA = 0.520). High stromal inflammation corresponded best with dichotomously assessed tumor-infiltrating lymphocytes when the cutoff was set at 10% (kappa = 0.881). Nevertheless, a post hoc tumor-infiltrating lymphocytes cutoff set at 20% resulted in the highest interobserver agreement (KA = 0.669). Despite upfront dichotomous evaluation, the interobserver variability remains considerable and is at most acceptable, although it varies among the different histopathological features. Future studies should investigate its impact on ductal carcinoma in situ prognostication. Forthcoming machine learning algorithms may be useful to tackle this substantial diagnostic challenge.

State of the Art on Kidney Development: How Nephron Endowment at Birth Can Shape Our Susceptibility to Renal Dysfunction Later in Life.

In the present article, we discuss the following topics: (1) the fetal programming of adult kidney diseases and (2) the role of neonatologists in the regenerative renal medicine, based on the activation of resident renal SC. Here, we report the most important steps of our collaboration between neonatologists, nephrologists, and pathologists. Nephrologists should be more interested in clinical data regarding the first month of life in the womb of their adult patients, being particularly focused on birth weight and on the weeks of gestation at birth, without forgetting data regarding maternal status during gestation and neonatal asphyxia. Neonatologists should be aware that any preterm or low birthweight infant should be considered as a subject with fewer glomeruli, probably predicted to develop renal disease later in life.

Prognostic value of age, subglottic, and anterior commissure involvement for early glottic carcinoma treated with CO2 laser transoral microsurgery: a retrospective, single-center cohort study of 261 patients.

PURPOSE:  CO2 laser transoral microsurgery for glottic carcinoma, when indicated, has the well-established advantages of low morbidity and positive oncological outcomes. The present study aims to determine how patient age, and tumor site could negatively impact prognosis; other variables such as the status of the margins of resection, tobacco and alcohol intake, and the grade of differentiation of the tumors have been evaluated. METHODS: This was a retrospective analysis on 261 patients with a glottic carcinoma who underwent CO2 laser transoral microsurgery. The impact of different variables was calculated using univariate and multivariate analyses. RESULTS: The study included 248 males and 13 females. The median follow-up period was 4.3 years. Five-year disease-specific survival, recurrence-free survival, local control with laser alone, overall laryngeal preservation, and overall survival rates were 99.4, 92.2, 93.8, 97.6, and 85.5%, respectively. Equivalent results were observed in young and elderly patients. Patients with positive margins after CO2 laser transoral microsurgery showed a reduced local control with laser alone. T2 patients with true subglottic spreading and patients with anterior commissure involvement of grade 3 (Rucci's classification) experienced worse local control rates, despite free surgical margins confirmed by histology. CONCLUSIONS:  CO2 laser transoral microsurgery is an effective and reproducible single-stage modality therapy for young and elderly patients with glottic carcinoma. Superficial close margins can be managed by a careful wait-and-see policy, while positive margins should undergo surgical enlargement. In our experience, undifferentiated tumors, true subglottic extension, and anterior commissure involvement of grade 3 were associated with worse outcomes.

Fetal programming of neuropsychiatric disorders.

Starting from the Developmental Origins of Health and Disease (DOHaD) hypotheses proposed by David Barker, namely fetal programming, in the past years, there is a growing evidence of the major role played by epigenetic factors during the intrauterine life and the perinatal period. Furthermore, it has been assessed that these factors can affect the health status in infancy and even in adulthood. In this review, we focus our attention on the fetal programming of the brain, analyzing the most recent literature concerning the epigenetic factors that can influence the development of neuropsychiatric disorders such as bipolar disorders, major depressive disorders, and schizophrenia. The perinatal epigenetic factors have been divided in two main groups: maternal factors and fetal factors. The maternal factors include diet, smoking, alcoholism, hypertension, malnutrition, trace elements, stress, diabetes, substance abuse, and exposure to environmental toxicants, while the fetal factors include hypoxia/asphyxia, placental insufficiency, prematurity, low birth weight, drugs administered to the mother or to the baby, and all factors causing intrauterine growth restriction. A better comprehension of the possible mechanisms underlying the pathogenesis of these diseases may help researchers and clinicians develop new diagnostic tools and treatments to offer these patients a tailored medical treatment strategy to improve their quality of life. Birth Defects Research (Part C) 108:207-223, 2016. © 2016 Wiley Periodicals, Inc.

Enhanced contact endoscopy for the assessment of the neoangiogenetic changes in precancerous and cancerous lesions of the oral cavity and oropharynx.

Dysplasia and squamous cell carcinoma of the upper aerodigestive tract show significant neoangiogenesis appearing as subepithelial and epithelial microvascular irregularities that can be detected by Image-Enhanced Endoscopy such as Narrow Band Imaging and Storz Professional Image Enhancement System. In the present study, the most advanced endoscopic enhancement systems were coupled with Contact Endoscopy (Enhanced Contact Endoscopy). This original method improved the identification and the understanding of the neoangiogenetic changes of the chorion in 42 patients with leukoplakia, erythroplakia, and leuko-erythroplakia of the oral cavity and oropharynx. The physiologic and pathologic mucosa was described in five obvious vascular patterns observed at Enhanced Contact Endoscopy ranging from normal to squamous cell carcinoma, passing through inflammation, hyperplasia, and dysplasia. Each vascular pattern was then compared to histology, showing that the microvascular architectural changes seen with Enhanced Contact Endoscopy are almost constant. Sensitivity, specificity, positive predictive value, and negative predictive value in the differentiation between healthy mucosa and inflammation versus pathologic hyperplasia, dysplasia, and carcinoma were, respectively, 96.6, 93.3, 98.2, 87.5, and 95.9 %. Sensitivity and specificity were 100 % in differentiation between non-malignant lesions versus squamous cell carcinoma. Our preliminary experience shows that accuracy of Image-Enhanced Endoscopy in the diagnosis of precancerous lesions and squamous cell carcinoma of the oral cavity and oropharynx can be increased if associated to Contact Endoscopy.

Surgical Management of Patients with Parotid Involvement from Non-Melanoma Skin Cancer of the Head and Neck.

We conducted a retrospective, longitudinal study on a single-center series of patients who underwent parotidectomy in the management of advanced head and neck non-melanoma skin cancer (hnNMSC). The aim of this study was to identify prognostic factors associated with worse outcomes. Forty-one men and nine women were included. The mean age at the time of surgery was 78.9 years. The 5-year overall survival, disease-specific survival, locoregional recurrence-free survival, and distant metastasis-free survival calculated with Kaplan-Meier curves were 39.9%, 56.3%, 58.6%, and 82.1%, respectively. A univariate analysis showed that the status of the margins, facial nerve direct involvement, lymph vascular invasion, and histological grading were associated with worse outcomes (p < 0.05). Positive margins were associated with worse disease-specific survival also in a multivariate analysis (p = 0.001, HR = 32.02, and CIs 4.338 to 351.3). Because the resection in free margins is the most important prognostic factor, early diagnosis or, in the case of advanced disease, extensive surgical resection with concomitant reconstruction is needed. Adjuvant therapy is indicated in selected cases.

Segmental Mandibulectomy and Mandibular Reconstruction with Fibula-Free Flap Using a 3D Template.

INTRODUCTION: The present study evaluates the influence of virtual surgical planning with a preoperative 3D resin model on aesthetic and functional outcomes in patients treated by segmental mandibulectomy and reconstruction with fibula-free flap for oral cancer. METHODS: All consecutive patients who underwent segmental mandibulectomy and mandibular reconstruction with a fibula-free flap using a 3D template at our department from January 2021 to January 2023 were included in the study. "Patients control" were patients treated by reconstruction with a fibula-free flap without using a 3D template. Three-dimensional modeling was performed by converting from preoperative computed tomography to a stereolithography format to obtain the resin 3D models. Qualitative analysis of anatomical and aesthetic results consisted of the evaluation of the patients' aesthetic and functional satisfaction and the symmetry of the mandibular contour observed at clinical examination. Quantitative analysis was based on the assessment of the accuracy and precision of the reconstruction by comparing preoperative and postoperative computed tomograms as objective indicators. RESULTS: Seven patients (five males and two females, mean age of 65.1 years) were included in the study. All patients showed a symmetric mandibular contour based on the clinical examination. After recovery, six patients (85.7%) considered themselves aesthetically satisfied. The quantitative analysis (assessed in six/seven patients) showed that the mean difference between preoperative and postoperative intercondylar distance, intergonial angle distance, anteroposterior dimension, and gonial angle improved in the 3D template-assisted group. CONCLUSION: The 3D-printed template for mandibular reconstruction with microvascular fibula-free flap can improve aesthetic outcomes in comparison with standard approaches.

Prediction of Response to Anti-Angiogenic Treatment for Advanced Colorectal Cancer Patients: From Biological Factors to Functional Imaging.

Colorectal cancer (CRC) is a leading tumor worldwide. In CRC, the angiogenic pathway plays a crucial role in cancer development and the process of metastasis. Thus, anti-angiogenic drugs represent a milestone for metastatic CRC (mCRC) treatment and lead to significant improvement of clinical outcomes. Nevertheless, not all patients respond to treatment and some develop resistance. Therefore, the identification of predictive factors able to predict response to angiogenesis pathway blockade is required in order to identify the best candidates to receive these agents. Unfortunately, no predictive biomarkers have been prospectively validated to date. Over the years, research has focused on biologic factors such as genetic polymorphisms, circulating biomarkers, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and microRNA. Moreover, research efforts have evaluated the potential correlation of molecular biomarkers with imaging techniques used for tumor assessment as well as the application of imaging tools in clinical practice. In addition to functional imaging, radiomics, a relatively newer technique, shows real promise in the setting of correlating molecular medicine to radiological phenotypes.

CD44 immunoreactivity in the developing human kidney: a marker of renal progenitor stem cells?

CD44 is a transmembrane adhesion glycoprotein, functioning as a hyaluronan receptor and participating in the uptake and degradation of hyaluronan. Recently, CD44 has been proposed in the adult kidney as a marker of activated glomerular parietal epithelial cells, the putative niche stem cells that, in case of damage to podocytes, might migrate inside the glomerular tuft and undergo transition to podocytes. Here, immunoreactivity for CD44 was tested in 18 human fetuses and newborns with a gestational age ranging from 11 to 39 weeks. CD44 immunoreactivity was observed in all but one developing kidneys, being localized in several renal cell types including intraglomerular, capsular, cortical and medullary interstitial cells and nerve cells. In some cases, CD44 marked scattered cells in nephrogenic subcapsular zone. Our data indicate that CD44 is involved in human nephrogenesis, probably marking a subset of progenitor/stem cells involved in early phases of kidney development and, putatively, in podocyte and/or interstitial cell differentiation.

Management and Oncologic Outcomes of Close and Positive Margins after Transoral CO2 Laser Microsurgery for Early Glottic Carcinoma.

BACKGROUND: The present study analyzed the impact of margin status on local control and survival, and the management of close/positive margins after transoral CO2 laser microsurgery for early glottic carcinoma. METHODS: 351 patients (328 males, 23 females, mean age 65.6 years) underwent surgery. We identified the following margin statuses: negative, close superficial (CS), close deep (CD), positive single superficial (SS), positive multiple superficial (MS), and positive deep (DEEP). RESULTS: A total of 286 patients (81.5%) had negative margins, 23 (6.5%) had close margins (8 CS, 15 CD) and 42 (12%) had positive margins (16 SS, 9 MS, 17 DEEP). Among the 65 patients with close/positive margins, 44 patients underwent enlargement, 6 radiotherapy and 15 follow-up. Twenty-two patients (6.3%) recurred. Patients with DEEP or CD margins showed a higher risk of recurrence (hazard ratios of 2.863 and 2.537, respectively), compared to patients with negative margins. Local control with laser alone, overall laryngeal preservation and disease-specific survival decreased significantly in patients with DEEP margins (57.5%, 86.9% and 92.9%, p < 0.05). CONCLUSIONS: Patients with CS or SS margins could be safely submitted to follow-up. In the case of CD and MS margins, any additional treatment should be discussed with the patient. In the case of DEEP margin, additional treatment is always recommended.

Non-invasive coronary imaging in elderly population.

Age is a non-modifiable cardiovascular risk factor, which leads to development and progression of chronic conditions, such as coronary artery disease, by promoting atherosclerosis. Aging is responsible for morphological structure changes of the coronary arteries and specific atherosclerotic plaque features, which can be studied with non-invasive coronary imaging techniques, particularly coronary CT angiography. The aim of this review is to evaluate current knowledge on this technique applied to the elderly population, and to describe CAD manifestation and plaque features of coronary atherosclerosis in this particular set of patients. We also discuss the clinical implication of frailty assessment and customization of diagnostic strategies in order to shift the approach from disease-centered to patient-centered care.

Bilateral selective laryngeal reinnervation in patients with bilateral vocal cord palsy.

Objective: Bilateral selective reinnervation of the larynx aims to restore both vocal cord tone and abductor movements in patients with bilateral vocal cord palsy. Methods: Four females and one male treated by bilateral selective reinnervation of the larynx were included in the present study. In all cases, both posterior cricoarytenoid muscles were reinnervated using the C3 right phrenic nerve root through the great auricular nerve graft, while adductor muscle tone was bilaterally restored using the thyrohyoid branches of the hypoglossal nerve through transverse cervical nerve grafts. Results: After a minimum follow-up of 48 months, all patients were successfully tracheostomy free and had recovered normal swallowing. At laryngoscopy, the first patient recovered a left unilateral partial abductor movement, the second had complete bilateral abductor movements, the third did not show improvements of abductor movements, but symptomatology was improved, the fourth recovered partial bilateral abductor movements and the fifth case did not show improvements and needed posterior cordotomy. Conclusions: Bilateral selective laryngeal reinnervation, although a complex surgical procedure, offers a more physiologic recovery in the treatment of bilateral vocal fold paralysis. Selection criteria still needs to be precisely defined to avoid unexpected failures.

Survival in Patients with Primary Parotid Gland Carcinoma after Surgery-Results of a Single-Centre Study.

This study aims to analyse a single-centre cohort series of patients who underwent parotidectomy for primary malignant parotid tumours. A retrospective chart review of 64 consecutive patients treated from November 2010 to March 2022 was performed. Outcomes were analysed by Kaplan-Meier curves. Sixty-four patients with a primary parotid malignancy were included in the study, with one bilateral case in this cohort. Patients were classified as stage I-II in 39 cases and stage III-IV in 26 cases. The five-year overall survival (OS), disease-specific survival (DSS), local relapse-free survival (LRFS), and distant metastasis-free survival (DMFS) rates were 78.4%, 89%, 92.5%, and 87.1%, respectively. Univariate analysis showed that high-risk histology, stage IV disease, lymphovascular invasion, perineural invasion, node metastasis, skin involvement, facial nerve involvement, and positive or close margins were risk factors associated with poorer outcomes. At present, the best evidence suggests that radical surgery should be the standard approach, and adjuvant therapy, in terms of radiotherapy/chemoradiotherapy, is recommended in patients with risk factors.

Effect of Radio-Chemotherapy on PD-L1 Immunohistochemical Expression in Head and Neck Squamous Cell Carcinoma.

BACKGROUND: Programmed death-ligand 1 (PD-L1) checkpoint inhibitors represent a mainstay of therapy in head and neck squamous cell cancer (HNSCC). However, little is known about the influence of combined therapy on PD-L1 expression. The study aims to gather evidence on this topic. METHODS: A systematic search was carried out in electronic databases Pubmed-MEDLINE and Embase to retrieve studies on the comparison of PD-L1 expression before and after conventional therapy. Data were extracted and a quantitative analysis with pooled odds ratios (ORs) was performed when applicable. RESULTS: Of 5688 items, 15 were finally included. Only a minority of studies assessed PD-L1 with the recommended combined positive score (CPS). The results are highly heterogeneous, with some studies reporting an increase in PD-L1 expression and others reporting a decrease. Three studies allowed for quantitative analysis and showed a pooled OR of 0.49 (CI 0.27-0.90). CONCLUSIONS: From the present evidence, a clear conclusion towards an increase or decrease in PD-L1 expression after combined therapy cannot be drawn, but even with few studies available, a trend towards an increase in expression in tumor cells at a cutoff of 1% can be noted in patients undergoing platinum-based therapy. Future studies will provide more robust data on the effect of combined therapy on PD-L1 expression.