Analogies between HPV Behavior in Oral and Vaginal Cavity: Narrative Review on the Current Evidence in the Literature.

Human genital papilloma virus infection is the most prevalent sexually transmitted infection in the world. It is estimated that more than 75% of sexually active women contract this infection in their lifetime. In 80% of young women, there is the clearance of the virus within 18-24 months. In developed countries, oral squamous cell carcinoma (OSCC) is now the most frequent human papilloma virus (HPV)-related cancer, having surpassed cervical cancer, and it is predicted that by 2030 most squamous cell carcinomas will be the HPV-related rather than non-HPV-related form. However, there are currently no screening programs for oral cavity infection. While the natural history of HPV infection in the cervix is well known, in the oropharynx, it is not entirely clear. Furthermore, the prevalence of HPV in the oropharynx is unknown. Published studies have found wide-ranging prevalence estimates of 2.6% to 50%. There are also conflicting results regarding the percentage of women presenting the same type of HPV at two mucosal sites, ranging from 0 to 60%. Additionally, the question arises as to whether oral infection can develop from genital HPV infection, through oral and genital contact or by self-inoculation, or whether it should be considered an independent event. However, there is still no consensus on these topics, nor on the relationship between genital and oral HPV infections. Therefore, this literature review aims to evaluate whether there is evidence of a connection between oral and cervical HPV, while also endorsing the usefulness of the screening of oral infection in patients with high-risk cervical HPV as a means of facilitating the diagnosis and early management of HPV-related oral lesions. Finally, this review emphasizes the recommendation for the use of the HPV vaccines in primary prevention in the male and female population as the most effective means of successfully counteracting the increasing incidence of OSCC to date.

Multicancer screening test based on the detection of circulating non haematological proliferating atypical cells.

BACKGROUND: the problem in early diagnosis of sporadic cancer is understanding the individual's risk to develop disease. In response to this need, global scientific research is focusing on developing predictive models based on non-invasive screening tests. A tentative solution to the problem may be a cancer screening blood-based test able to discover those cell requirements triggering subclinical and clinical onset latency, at the stage when the cell disorder, i.e. atypical epithelial hyperplasia, is still in a subclinical stage of proliferative dysregulation. METHODS: a well-established procedure to identify proliferating circulating tumor cells was deployed to measure the cell proliferation of circulating non-haematological cells which may suggest tumor pathology. Moreover, the data collected were processed by a supervised machine learning model to make the prediction. RESULTS: the developed test combining circulating non-haematological cell proliferation data and artificial intelligence shows 98.8% of accuracy, 100% sensitivity, and 95% specificity. CONCLUSION: this proof of concept study demonstrates that integration of innovative non invasive methods and predictive-models can be decisive in assessing the health status of an individual, and achieve cutting-edge results in cancer prevention and management.

Oxytocin augmentation and neurotransmitters in prolonged delivery: An experimental appraisal.

The uterus is a highly innervated organ, and during labor, this innervation is at its highest level. Oxytocinergic fibers play an important role in labor and delivery and, in particular, the Lower Uterine Segment, cervix, and fundus are all controlled by motor neurofibers. Oxytocin is a neurohormone that acts on receptors located on the membrane of the smooth cells of the myometrium. During the stages of labor and delivery, its binding causes myofibers to contract, which enables the fundus of the uterus to act as a mediator. The aim of this study was to investigate the presence of oxytocinergic fibers in prolonged and non-prolonged dystocic delivery in a cohort of 90 patients, evaluated during the first and second stages of labor. Myometrial tissue samples were collected and evaluated by electron microscopy, in order to quantify differences in neurofibers concentrations between the investigated and control cohorts of patients. The authors of this experiment showed that the concentration of oxytocinergic fibers differs between non-prolonged and prolonged dystocic delivery. In particular, in prolonged dystocic delivery, compared to non-prolonged dystocic delivery, there is a lower amount of oxytocin fiber. The increase in oxytocin appeared to be ineffective in patients who experienced prolonged dystocic delivery, since the dystocic labor ended as a result of the altered presence of oxytocinergic fibers detected in this group of patients.

Incidence of pre-neoplastic and neoplastic lesions of the cervix before and after the COVID-19 pandemic.

OBJECTIVE: The COVID-19 pandemic had significant effects on healthcare systems worldwide, including the disruption of routine screening programs for cervical cancer. This study aimed to compare the incidence of cervical intra-epithelial neoplasia (CIN)2 and CIN3 lesions, adenocarcinoma, and squamous carcinoma of the cervix before and after the COVID-19 pandemic. METHODS: A retrospective analysis was performed using archive data from the Policlinico di Bari, Unit of Gynecology and Obstetrics. The study included patients who tested positive for high-risk human papillomavirus (HPV) at the level I screening test (HPV test) and were subsequently referred to level II screening, which involves the Papanicolaou (Pap) test and colposcopic examination. We excluded individuals who did not comply with the recommended follow-up, patients with low-risk HPV infection, those with autoimmune diseases, oncologic diseases, or those undergoing immunosuppressive therapies. The time period spanned from January 2020 to December 2022. The incidence of CIN2/CIN3 lesions, adenocarcinoma, and squamous carcinoma of the cervix was compared between the pre-screening period (2017-2019) and the post-screening period (2020-2022). RESULTS: The study comprised a cohort of 1558 consecutive European sexually active women with a median age of 34 years (range 25-65) who underwent colposcopic evaluation of the uterine cervix as a level II screening program. The comparison between the pre-screening and post-screening periods showed an increase in the incidence of CIN2/CIN3 lesions, rising from 23.9 to 63.3 per 100 000 (HR 2.62, 95% CI 1.64 to 4.20; p<0.001). Additionally, although there was an absolute increase in the incidence of cervical carcinoma and adenocarcinoma, the comparison did not reach statistical significance (squamous carcinoma: 2017-2019, 2.5 per 100 000; 2020-2022 3.4 per 100 000, p=0.72; adenocarcinoma: 2017-2019, 3.5 per 100 000; 2020-2022 7.6 per 100 000, p=0.24). CONCLUSION: This study showed a significant increase in the incidence rate of CIN2/CIN3 lesions after the COVID-19 pandemic. Our findings may be attributed to the temporary suspension of follow-up programs during the pandemic, although the study does not rule out direct effects of SARS-CoV-2 on the risk of pre-neoplastic and neoplastic conditions of the cervix.

SARS-CoV-2 Infection in the Second Trimester of Pregnancy: A Case Report of Fetal Intraventricular Hemorrhage After Critical COVID-19 Infection and a Brief Review of the Literature.

More than three and a half years have passed since the start of the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and there have been several studies in the literature about the different damage and symptom patterns related to the condition; particular attention has been paid to the transmission of the disease from pregnant mothers to fetus. In this report, we present the case of a 36-year-old patient with a history of two cesarean sections (CS), two miscarriages, and hypothyroidism on replacement therapy, who contracted COVID-19 during the 15th week of gestation. Ultrasound (US) examination at 22 weeks revealed regular fetal biometry and bilateral ventriculomegaly, highly suggestive of massive intracerebral hemorrhage. The patient opted for the interruption of pregnancy. Given the critical maternal COVID-19 complications, especially tracheoesophageal fistula and the patient's two previous cesareans, we decided on an abortive CS at 23 weeks of gestation, and the samples were sent to the Pathology Department. Histologic analysis showed massive intervillous deposition of fibrin and inflammatory infiltration with hotspots of necrotic deciduitis and confirmed massive cerebral hemorrhage in the fetus. This morphological appearance was consistent with COVID-19 infection and probable fetal oxygenation compromise related to deciduitis. Immunoexpression of anti-SARS-CoV-2 S1 antibody was almost entirely positive at the level of syncytiotrophoblast cells and maternal leukocytes in the absence of a clear signal in the fetal circulation. Conversely, in the brain, immunoexpression of angiotensin-converting enzyme 2 (ACE2) and the S1 subunit of the spike protein of SARS-CoV-2, detected by a monoclonal antibody, was almost entirely negative, suggesting that there was no infection in the brain and that the massive intraventricular hemorrhage was probably a secondary effect of placental damage.

"The Strange Case of Dr Pump and Mr Acardiac": The Twin Reversed Arterial Perfusion (TRAP) Sequence in Two Monochorionic Monoamniotic (MCMA) Twin Pregnancies-Diagnosis, Prognosis and Management: Review of Literature.

The Twin Reversed Arterial Perfusion (TRAP) Sequence is an extremely rare complication of monochorionic twin pregnancies, with one severely malformed twin (the "acardiac") lacking autonomous placental blood supply and being perfused by the co-twin (the "pump"), through arterio-arterial (and sometimes also veno-venous) vascular anastomoses located on the placental surface. The prognosis is poor: mortality is 100% in the acardiac twin because of its severe malformations and about 50-55% in the pump twin, mainly due to heart failure and prematurity. So, the goal of perinatal management of the TRAP twin pregnancy is to deliver a healthy and near-term pump twin without heart failure or fetal hydrops. Intuitively, the earlier the diagnosis, the better the outcome. Herein, we report two cases of monochorionic monoamniotic (MCMA) twin pregnancies complicated by the TRAP Sequence, which are of interest since the objective of early diagnosis was achieved by means of transvaginal and 3D ultrasound, two techniques which revealed themselves as being useful to this purpose but are underused in the literature. The second aim of this study is to provide an overview of literature data about the diagnosis, prognosis establishment, and management of this rare condition, which are still debated and unclear due to negligible poor-quality evidence.

Cutaneous Metastasis from Internal Malignancies: The Revealing Role of the Skin.

Skin represents the heaviest organ of the human body, covering a surface area of 1 [...].

Inadvertent Administration of 72 µg of Follitropin-Δ for Three Consecutive Days Does Not Appear to Be Dangerous for Poor Responders: A Case Series.

Follitropin delta (Δ) is a recombinant human follicle-stimulating hormone (rFSH), like natural human FSH, that can stimulate the development and growth of multiple follicles. Treatment with Follitropin-Δ may cause mild to severe adverse reactions, such as the risk of developing ovarian hyperstimulation syndrome, resulting in nausea, vomiting and diarrhea, weight loss, respiratory difficulty, stomach swelling and discomfort of the pelvic area, headaches, and fatigue. To date, the effects of a Follitropin-Δ overdosage are unknown, and no data are reported in the scientific literature or in the drug data sheet. Therefore, this study aimed to describe the effects of Follitropin-Δ overdosages in poorly responding women who underwent IVF cycles. This is a descriptive case series of four nulligravid, poorly responding patients, two of whom made requests for fertility preservation. Four poorly responding patients who were prescribed 20.0 µg/day of Follitropin-Δ for three consecutive days wrongly injected the total cartridge of 72 µg Follitropin-Δ every day. After the incorrect injection of Follitropin-Δ, the patients continued their controlled ovarian stimulation and underwent vaginal ovarian pick up. The analyzed patients had no side effects or adverse reactions. The evaluations reported in this case series showed that the accidental use of 72 µg/day of Follitropin-Δ for three days did not cause side effects or adverse reactions in poor responders.

Efficacy of Systematic Early-Second-Trimester Ultrasound Screening for Facial Anomalies: A Comparison between Prenatal Ultrasound and Postmortem Findings.

Second-trimester 2D ultrasound (US) assessment of the fetal anatomy, as proposed by worldwide guidelines, allows detecting the majority of fetal malformation. However, the detection rates of fetal facial anomalies seem to still be low, mostly in cases of isolated facial malformation. The purpose of this research was to assess and analyze the concordance between the antenatal imaging findings from second-trimester US screening and the results of fetal postmortem autopsy. Between January 2010 and January 2020, there were 43 cases where fetuses with prenatal ultrasound diagnosis of a face abnormality, associated or not with a genetic syndrome or chromosomal disorder, following intrauterine death (IUD) or termination of pregnancy (TOP) after the 13 weeks of pregnancy, underwent autopsy in the Pathological Anatomy section of Bari Polyclinic specializing in feto-placental autopsies. The diagnosis of the fetal facial defects at ultrasound was compared with the findings at autopsy in all cases. A very high level of agreement between prenatal ultrasound and autopsy findings was found for facial abnormalities associated with genetic syndromes or numerical abnormality of chromosomes. A lower level of concordance was instead found in isolated facial defects or those associated with other organ anomalies, but not associated with genetic syndrome or numerical chromosome anomaly. A detailed examination of aborted fetuses led to successful quality control of early-second-trimester ultrasound detection of facial anomalies; however, it was less accurate for the isolated ones. It is, thus, reasonable to propose a systematic early-second-trimester prenatal ultrasound screening for facial anatomy by operators specialized in fetal medicine field, using 2D, 3D, and 4D techniques (two-, three-, and four-dimensional ultrasound).

Uterine venous malformations in the puerperium: 2 Atypical cases and literature review.

Uterine arteriovenous malformations (AVMs) is a rare but high-risk cause of uterine bleeding. The clinical management of this condition is challenging, as the ultrasound picture can sometimes be unambiguously interpreted. Moreover, in the puerperium in which acquired AVMs are most frequently formed, it is necessary to discuss the correct management in a multidisciplinary and personalized manner. We present two cases of AVMs developing in the puerperium, both with a vaginal delivery and spontaneous and complete secondment. The symptom of onset was an episode of bright red blood loss in the puerperium, on the 14th and 21st postpartum days, respectively. Transvaginal ultrasound showed a hypervascularized lesion in the myometrium with turbulent vascular flow, confirmed by transabdominal ultrasound and angiography. To date, there are no guidelines on the management of MAVs. In our cases we opted for a conservative approach, in order to preserve the fertility of the patient. These experiences reported have the purpose of enriching a literature still sparse on the subject and in the future to be able to represent a fulcrum for official recommendations.

Current evidence on diagnosis and treatment of parotid gland lymphomas: a systematic review.

BACKGROUND AND PURPOSE: Parotid gland lymphoma (PGL) is a rare and challenging diagnosis. Different lymphomas can develop in the parotid gland, with the most common being the mucosa-associated lymphoid tissue (MALT) lymphoma, which originates directly from the glandular parenchyma. Other histologic subtypes arise from both intraglandular and extraglandular parotid lymph nodes. A consensus on diagnosis and treatment of PGL is still lacking, and published data is scarce and heterogeneous. METHODS: We performed a systematic review of the literature, including studies published after 2001, when the WHO classification of lymphoid tumours was introduced. RESULTS: Twenty retrospective studies were included in the analyses, eight of which focused exclusively on MALT lymphomas. Final analysis included 612 cases of PGL, with a 1.68:1 F/M ratio. MALT lymphoma was the most common histology, followed by follicular and diffuse large B-cell lymphoma. Most cases were low stages (IE/IIE acc. Ann Arbour, 76.5%) and only 10% of patients presented with symptoms, most commonly pain (4.8%) and B symptoms (2.2%). A high prevalence of associated autoimmune diseases was found, particularly Sjögren's syndrome, that affected up to 70% of patients with MALT lymphoma. In most cases diagnosis was achieved through parotidectomy (57.5%), or open biopsy (31.2%). Treatment strategies were either surgical, non-surgical or a combination of modalities. Surgery as a single-modality treatment was reported in about 20% of patients, supposing it might be a valuable option for selected patients. CONCLUSIONS: Our review showed that the diagnosis and treatment of PGLs is far from being standardized and needs further, more homogeneous reports to reach consensus.

Office intrauterine morcellation for retained products of conception.

OBJECTIVE: Proposing hysteroscopic morcellation (HM) as a surgical-therapeutic approach in the treatment of retained products of conception (RPOC) to prevent intrauterine adhesions (IUAs). DESIGN: Prospective analysis. SETTING: A teaching and university hospital. PATIENTS: Women with RPOC. INTERVENTIONS: Office -HM with 'Truclear 5 C'. MATERIAL AND METHODS: Twenty-two consecutive patients presenting with trophoblastic residue retention after miscarriage and interruption of pregnancy or placenta remnants after cesarean section or delivery were enrolled. These women underwent office-HM with 'Truclear 5 C'. Primary outcomes were median time and rate of hospitalization. The quality of the specimen was also analyzed. A hysteroscopic second look for IUAs was performed. RESULTS: Mean procedure time was six minutes (SD ± 5). Tissue samples had a mean collection size 2.5 cm3+0.9. 38% of the samples had spotting or abnormal vaginal discharge. Dilatation of the cervical canal was not performed in any case. Second-look hysteroscopy did not show any de novo IUAs in any of the enrolled patients. CONCLUSIONS: In the hysteroscopic treatment of RPOC, HM is a valid choice in an office setting without the use of cervical dilatation. Removal of RPOC was uneventful in all cases, simple and carried out faster without any adverse outcomes.

"Lights and Shades" of Fertility Preservation in Transgender Men Patients: A Clinical and Pathological Review.

Fertility preservation (FP) is becoming a critical issue in transgender men who desire biological offspring in the future. The prevalence of transgender individuals in the United States is increasing, and as a result, the demand for gender-affirming surgeries (GAS) and associated FP techniques is rising. Despite the growing demand, there is currently no personalized approach to FP for transgender men, and the available techniques have limitations that require further investigation. In the present review we carefully examine the existing literature on this topic to highlight the shortcomings of current methods and areas where additional research is needed to advance the field. Hormonal therapy (HT), which is an integral part of gender transition in transgender men, can have a significant impact on fertility and may increase the risk of various diseases. Moreover, GAS usually leads to permanent sterility in these patients. Therefore, it is essential to provide patients with accurate information about the benefits and potential risks of different FP techniques, taking into account the patient's reproductive goals. This review underscores the complex and multifaceted nature of FP in transgender men and emphasizes the need for further research to develop more effective and personalized approaches to FP for this population.

Upgrading Treatment and Molecular Diagnosis in Endometrial Cancer-Driving New Tools for Endometrial Preservation?

One emerging problem for onco-gynecologists is the incidence of premenopausal patients under 40 years of age diagnosed with stage I Endometrial Cancer (EC) who want to preserve their fertility. Our review aims to define a primary risk assessment that can help fertility experts and onco-gynecologists tailor personalized treatment and fertility-preserving strategies for fertile patients wishing to have children. We confirm that risk factors such as myometrial invasion and The International Federation of Gynecology and Obstetrics (FIGO) staging should be integrated into the novel molecular classification provided by The Cancer Genome Atlas (TCGA). We also corroborate the influence of classical risk factors such as obesity, Polycystic ovarian syndrome (PCOS), and diabetes mellitus to assess fertility outcomes. The fertility preservation options are inadequately discussed with women with a diagnosis of gynecological cancer. A multidisciplinary team of gynecologists, oncologists, and fertility specialists could increase patient satisfaction and improve fertility outcomes. The incidence and death rates of endometrial cancer are rising globally. International guidelines recommend radical hysterectomy and bilateral salpingo-oophorectomy as the standard of care for this cancer; however, fertility-sparing alternatives should be tailored to motivated women of reproductive age, establishing an appropriate cost-benefit balance between childbearing desire and cancer risk. New molecular classifications such as that of TCGA provide a robust supplementary risk assessment tool that can tailor the treatment options to the patient's needs, curtail over- and under-treatment, and contribute to the spread of fertility-preserving strategies.

PReferentially Expressed Antigen in MElanoma (PRAME): preliminary communication on a translational tool able to early detect Oral Malignant Melanoma (OMM).

Oral malignant melanoma (OMM) has a prevalence less than 1% of all melanomas and it commonly develops on the oral mucosa following a slow and unspecific transformation of unstable melanocytic lesions, often resulting in a diagnostic delay. The marker PReferentially Expressed Antigen in MElanoma (PRAME) seems to be a valid tool to investigate the biological and histological nature of cutaneous melanocytic lesions, but to date its use to characterize pigmented lesions in the oral cavity is largely unexplored. The aim of this study was to create preliminary knowledge on the PRAME expression in OMM, and to compare its expression respect to other dysplastic pigmented lesions of the oral cavity. Interestingly, PRAME has been demonstrated to be reliable in the clinical conditions investigated in our pilot study; in fact, it has clearly differentiated the cases of Melanoma, which showed diffuse and intense positivity (score 6+/7+) to PRAME, from the other melanocytic nevi, which resulted to be mainly negative to PRAME. This means a better differential diagnosis, a reliable early diagnosis and a proper clinical/surgical management of the oncological lesions. In conclusion, PRAME can be a valid qualitative marker for differential diagnosis, not only in cutaneous melanomas, but also in malignant melanoma of the entire head and neck area.

A Multi-Institutional Informed Consent Proposal as a Prevention Tool for Combined Oral Contraceptive Intake and Thrombotic Risk.

Combined oral contraceptives (COC), are among the most widely used contraceptive methods in the world today. Despite the different changes in terms of estrogen/progestogen combinations and dosages, the thromboembolic risk for a woman who takes combined oral contraceptives persists to date. METHODS: The review of relevant literature and international guidelines on prescription of combined oral contraceptives made it possible to create a proposal for informed consent to be used for prescribing. RESULTS: The several sections of our consent proposal were designed according to a rationale in order to cover all the aspects presented by worldwide guidelines: how to take, adverse effects, advertisements, extra-contraceptive benefits and effects, a checklist for condition at risk of thromboembolism, the signature of the woman. CONCLUSIONS: An informed consent to standardize combined oral contraceptives prescription can improve women's eligibility, mitigate thromboembolic risk, and assure legal protection to healthcare providers. In this systematic review in particular, we refer to the Italian medical-legal scenario, to which our group of researchers belongs. However, the model proposed was designed in the respect of main healthcare organization guidelines, and it could be easily used by any center in the world.

Heat Stroke in the Work Environment: Case Report of an Underestimated Phenomenon.

Average global temperatures continue to trend upward, and this phenomenon is part of the more complex climate change taking place on our planet over the past century. Human health is directly affected by environmental conditions, not only because of communicable diseases that are clearly affected by climate, but also because of the relationship between rising temperatures and increased morbidity for psychiatric diseases. As global temperatures and the number of extreme days increase, so does the risk associated with all those acute illnesses related to these factors. For example, there is a correlation between out-of-hospital cardiac arrest and heat. Then, there are pathologies that recognize excessive heat as the main etiological agent. This is the case with so-called "heat stroke", a form of hyperthermia accompanied by a systemic inflammatory response, which causes multi-organ dysfunction and sometimes death. Starting with a case that came to their attention of a young man in good general health who died while working unloading fruit crates from a truck, the authors wanted to express some thoughts on the need to adapt the world of work, including work-specific hazards, in order to protect the worker exposed to this "new risk" and develop multidisciplinary adaptation strategies that incorporate climatology, indoor/building environments, energy use, regulatory perfection of work and human thermal comfort.

T Cell Immunoglobulin and Mucin Domain 3 (TIM-3) in Cutaneous Melanoma: A Narrative Review.

T cell immunoglobulin and mucin domain 3 (TIM-3) is an inhibitory immunocheckpoint that belongs to the TIM gene family. Monney et al. first discovered it about 20 years ago and linked it to some autoimmune diseases; subsequent studies have revealed that some tumours, including melanoma, have the capacity to produce inhibitory ligands that bind to these receptor checkpoints on tumour-specific immune cells. We conducted a literature search using PubMed, Web of Science (WoS), Scopus, Google Scholar, and Cochrane, searching for the following keywords: "T cell immunoglobulin and mucin-domain containing-3", "TIM-3" and/or "Immunocheckpoint inhibitors" in combination with "malignant melanoma" or "human malignant melanoma" or "cutaneous melanoma". The literature search initially turned up 117 documents, 23 of which were duplicates. After verifying eligibility and inclusion criteria, 17 publications were ultimately included. A growing body of scientific evidence considers TIM-3 a valid inhibitory immuno-checkpoint with a very interesting potential in the field of melanoma. However, other recent studies have discovered new roles for TIM-3 that seem almost to contradict previous findings in this regard. All this demonstrates how common and valid the concept of 'pleiotropism' is in the TME field, in that the same molecule can behave completely or partially differently depending on the cell type considered or on temporary conditions. Further studies, large case series, and a special focus on the immunophenotype of TIM-3 are absolutely necessary in order to explore this highly promising topic in the near future.

Mutated axon guidance gene PLXNB2 sustains growth and invasiveness of stem cells isolated from cancers of unknown primary.

The genetic changes sustaining the development of cancers of unknown primary (CUP) remain elusive. The whole-exome genomic profiling of 14 rigorously selected CUP samples did not reveal specific recurring mutation in known driver genes. However, by comparing the mutational landscape of CUPs with that of most other human tumor types, it emerged a consistent enrichment of changes in genes belonging to the axon guidance KEGG pathway. In particular, G842C mutation of PlexinB2 (PlxnB2) was predicted to be activating. Indeed, knocking down the mutated, but not the wild-type, PlxnB2 in CUP stem cells resulted in the impairment of self-renewal and proliferation in culture, as well as tumorigenic capacity in mice. Conversely, the genetic transfer of G842C-PlxnB2 was sufficient to promote CUP stem cell proliferation and tumorigenesis in mice. Notably, G842C-PlxnB2 expression in CUP cells was associated with basal EGFR phosphorylation, and EGFR blockade impaired the viability of CUP cells reliant on the mutated receptor. Moreover, the mutated PlxnB2 elicited CUP cell invasiveness, blocked by EGFR inhibitor treatment. In sum, we found that a novel activating mutation of the axon guidance gene PLXNB2 sustains proliferative autonomy and confers invasive properties to stem cells isolated from cancers of unknown primary, in EGFR-dependent manner.