Risk of Melanoma in Patients with Basal Cell Carcinoma: A Population-based Cohort Study.

Basal cell carcinoma is the most prevalent cancer in Caucasians worldwide. The aim of this study was to examine the overall risk of melanoma among patients diagnosed with basal cell carcinoma. This population-based retrospective cohort study included data from January 2010 to December 2018 from the databases of the Clalit Health Maintenance Organization and 2 major pathology laboratories in North District, Israel. The incidence and hazard ratio of melanoma in patients with a diagnosis of basal cell carcinoma were determined. Of 466,700 participants, 51% were women and the mean (standard deviation) follow-up was 6.7 (2.9; range 1-9) years. A total of 3,338 patients were diagnosed with basal cell carcinoma during the study period, 82 of whom subsequently developed melanoma. Patients with basal cell carcinoma had a significantly higher incidence of melanoma than patients without basal cell carcinoma (2.46% vs 0.37%; p < 0.0001). Univariate Cox regression analysis revealed a hazard ratio of 6.6 (95% confidence interval: 3.6-12.1; p < 0.0001) for melanoma in patients with a diagnosis of basal cell carcinoma. In conclusion, a diagnosis of basal cell carcinoma confers a significant risk of melanoma.

COG6-CDG: Expanding the phenotype with emphasis on glycosylation defects involved in the causation of male disorders of sex development.

COG6-congenital disorder of glycosylation (COG6-CDG) is caused by biallelic mutations in COG6. To-date, 12 variants causing COG6-CDG in less than 20 patients have been reported. Using whole exome sequencing we identified two siblings with a novel homozygous deletion of 26 bp in COG6, creating a splicing variant (c.518_540 + 3del) and a shift in the reading frame. The phenotype of COG6-CDG includes growth and developmental retardation, microcephaly, liver and gastrointestinal disease, hypohydrosis and recurrent infections. We report two patients with novel phenotypic features including bowel malrotation and ambiguous genitalia, directing attention to the role of glycoprotein metabolism in the causation of disorders of sex development (DSD). Searching the glycomic literature, we identified 14 CDGs including males with DSD, a feature not previously accentuated. This study broadens the genetic and phenotypic spectrum of COG6-CDG and calls for increasing awareness to the central role of glycosylation processes in development of human sex and genitalia.

Detection of high-risk human papillomavirus in the tonsils of galilee region adults and young adults undergoing tonsillectomy.

INTRODUCTION: The presence of high-risk HPV in non-malignant tonsil tissues from patients who underwent tonsillectomy in the Galilee area might explain the low incidence of HPV-related oropharyngeal malignancy in the country. The aim of this retrospective study was to study the prevalence of human papillomavirus (HPV) in non-malignant tonsillectomy specimens of adults in the Galilee area. MATERIALS AND METHODS: We conducted a retrospective analysis of all tonsil samples in our medical center. Tonsils from patients over 20 years of age who underwent tonsillectomy for the indication of recurrent tonsillitis and sleep apneas were eligible. Samples of formalin-fixed paraffin-embedded (FFPE) tonsillar tissue were tested for the presence of HPV DNA using polymerase chain reaction and by p16 immunohistochemistry. RESULTS: Of the 71 tonsil samples, age range 20-65, none were positive for HPV DNA. Fifty-two FFPE specimens of tonsil with HPV-positive cancer tested positive by the same method served as positive controls. CONCLUSIONS: HPV DNA is rare in non-malignant tonsil tissues of young adults and adults who underwent tonsillectomy in the Galilee area. Further research should be done in larger cohorts.

Detection and dissection of sentinel nodes in endometrial endometrioid cancer with indocyanine green using PinPoint laparoscopy: Analysis of the learning curve.

OBJECTIVE: Early-stage endometrial endometrioid adenocarcinoma is managed through laparoscopic total hysterectomy with bilateral salpingo-oophorectomy and pelvic lymphadenectomy. Detection of positive nodes is rare, and lymphadenectomy may involve complications. Pelvic sentinel lymph node dissection can prevent complete dissection. Herein, we evaluated the learning curve of sentinel lymph node dissection using indocyanine green. STUDY DESIGN: All surgeries for endometrial endometrioid adenocarcinoma were performed laparoscopically with indocyanine green to detect sentinel nodes. The primary outcome was the ability to identify and resect sentinel lymph nodes on each side. The secondary outcome was correspondence between the frozen section histology of the nodes with the final histology. RESULTS: Among 31 patients with endometrial endometrioid adenocarcinoma treated between October 2018 and August 2020, 29 who underwent laparoscopy using indocyanine green were enrolled. Complete lymphadenectomy was performed in 16 patients. Failure to recognize sentinel nodes on right and left sides occurred in 10.34% and 0% of cases, respectively. The median number of recognized and dissected sentinel nodes was 1 on both sides (range 0-5). One patient had a lymph node positive for malignancy on histology (3.45%) on both sides. There were 13 and 14 cases of negative frozen sections on the right and left sides, respectively, and 1 case of a positive frozen section with positive whole pelvic lymph nodes. CONCLUSION: Sentinel node dissection using indocyanine green in endometrial endometrioid adenocarcinoma has a distinct learning curve; however, it is practical and achievable for skilled surgeons.

Nonelectric shaving of endometrial polyp by hysteroscopy - A new technique to eliminate thermal damage.

OBJECTIVE: To present a new technique for complete endometrial polypectomy, using the bipolar loop hysteroscope, but without the activation of electrical energy, and follow its efficiency and safety for the patient. STUDY DESIGN: This is a prospective descriptive study conducted at a university hospital. Forty four patients were recruited to the study according to an intra uterine polyp diagnosed by transvaginal ultrasound (TVS). Out of them 25 really had an endometrial polyp which was inspected by hysteroscopy. Eighteen were at menopause age and seven in their reproductive age. The hysteroscopic removal of the endometrial polyp was performed using the operative loop resectoscope without using electricity, meaning by cold loop. We called this unique technique SHEPH: Shaving of Endometrial Polyp by Hysteroscopy. RESULTS: The range age was 21-77 years old. All patients with apparently endometrial polyp, underwent a complete removal of the polyp which could be directly seen through hysteroscopy. No bleeding was seen in all cases. The other nineteen patients had normal uterine cavity, so a biopsy was taken according to the indication. The specimen from all cases were sent to histological evaluation. An endometrial polyp was histologically confirmed in all cases who underwent the SHEPH technique, while fragments of an endometrial polyp was revealed by histology in six cases from the group that had normal uterine cavity. No complications were noted for the short and long periods. CONCLUSIONS: Nonelectric Shaving of Endometrial Polyp by Hysteroscopy (SHEPH technique) is a safe and effective procedure which allows the surgeon to achieve a complete endometrial polypectomy but without using electrical energy within the body of the patient. The technique which is easy to learn, is new and unique by eliminate thermal damage in a very common gynecologic indication.

Revealing the uterine blood vessel network via virtual pathology.

BACKGROUND: The distribution of the blood vessel network at any point in time in any body tissue, may provide valuable information with regards to the tissue condition and its angiogenesis functionality. The blood vessel three-dimensional network of the endometrium goes through a process of change over a relatively short period of 4 weeks on average. It is well accepted that this angiogenesis is closely related to the success or failure of the implantation of the embryo Objective and rationale: Our study aims to present a method to follow the three-dimensional evolution of the superficial blood vessel distribution in the endometrium throughout the uterine cycle. METHOD: This method utilizes differences in the observed broadband colors of the blood vessels in order to assess their depth coordinate below the endometrial tissue surface. We implemented the method using microscopic images of fresh, ex-vivo, endometrial samples of different cycle days to obtain the statistical evolution track of the superficial blood vessel population in both human and animal (swine) samples. OUTCOMES: In human samples we observed a systematic and consistent trend in the BV diameter distribution at different tissue depths. We demonstrate that the magnitude of this trend evolves throughout the course of the female cycle. WIDER IMPLICATIONS: This method has the potential to further our understanding of the mechanisms of angiogenesis in tissues other than the endometrium. We propose that this method may also contribute to more precise endometrial dating and may assist in more accurate determination of embryo transfer timing within IVF treatments.

A new method for endometrial dating using computerized virtual pathology.

Endometrial dating (ED) is the process by which the menstrual cycle day is estimated and is an important tool for the evaluation of uterine status. To date, ED methods remain inaccurate and controversial. We demonstrate how the rise of computerized virtual histology changes the state of affairs and introduce a new ED method. We present the results of a clinical trial where magnified images of ex-vivo endometrial tissue samples were captured at different cycle days, together with measurements of serum hormone levels on the same day. Patient testimonies about their cycle day were also collected. Computerized image analysis, followed by statistical representation of the tissue features, allowed mathematical representation of the cycle day. The samples underwent ED histological assessment, which is currently the ED gold standard. We compared dating results from patient reports, serum hormone levels, and histology to establish their concordance level. We then compared histology-based ED with the new method ED in the secretory phase (i.e. post ovulation). The correlation coefficient between the two resulted in an R = 0.89 with a P-value of P < 10-4. The new method, Virtual Pathology Endometrial Dating (VPED), has the benefit of being a real time, in-vivo method that can be repeatedly applied without tissue damage, using a dedicated hysteroscope. One practical use of this method may be the determination of accurate real-time embryo transfer timing in IVF treatments.

Term and preterm (<34 and <37 weeks gestation) placental pathologies associated with fetal growth restriction.

OBJECTIVE: The present study was aimed to compare term versus preterm placental pathologies associated with fetal growth restriction (FGR). STUDY DESIGN: A retrospective cohort study was performed, including all singleton deliveries of FGR with placental pathology examination. Comparison of placental findings was performed between neonates who were born at term versus preterm. Preterm was defined as <37 completed weeks of gestation, and <34 weeks gestation in another analysis. When one or more of the following pathology was found in microscopic examination of the placental tissue, the term uteroplacental insufficiency was defined: placental infarct, fibrosis of chorionic villi, thickening of blood vessels and poor vascularity of the chorionic villi. RESULTS: Macroscopic placental findings were available for 1,104 singleton FGR neonates; of these, 395 placentas had microscopic examinations. A significant greater proportion of preterm FGR cases had pathology findings associated with uteroplacental insufficiency as compared to term FGR (29.4 vs. 36.7%; OR = 1.4 95%, CI = 1.05-1.9; P = 0.019). The same pattern was seen while comparing placentas of FGR neonates who were born before and after 34 weeks (32.4 vs. 39.4%; OR = 1.4, 95% CI 1.02-1.8; P = 0.028). Syncytial knots were significantly more common in placentas from neonates who were delivered before 34 weeks of pregnancy (15.2 vs. 6.3%; OR = 2.6, 95% CI 1.3-5.6; P = 0.005). This trend was not statistically significant while comparing FGR before and after 37 weeks gestation (10.9 vs. 4.6%; OR = 2.4, 95% CI 0.99-7.7; P = 0.052). Meconial impregnation was more common among term versus preterm FGR neonates <37 weeks (22.4% vs. 7.2% OR = 3.7, 95% CI 2.3-5.9; P < 0.001), as well as among neonates who were born before and after 34 weeks of gestation (14.5 vs. 5.9%; OR = 0.4, 95% CI 0.2-0.6; P < 0.001). CONCLUSIONS: Placentas of preterm FGR neonates (either <37 weeks or <34 weeks gestation) reveal numerous pathologies reflecting uteroplacental insufficiency and abnormal blood supply. The presence of increased syncytial knots in preterm FGR neonates is probably due to exposure to hypoxia and reactive oxygen agents.

SMURF2 prevents detrimental changes to chromatin, protecting human dermal fibroblasts from chromosomal instability and tumorigenesis.

E3 ubiquitin ligases (E3s) play essential roles in the maintenance of tissue homeostasis under normal and stress conditions, as well as in disease states, particularly in cancer. However, the role of E3s in the initiation of human tumors is poorly understood. Previously, we reported that genetic ablation of the HECT-type E3 ubiquitin ligase Smurf2 induces carcinogenesis in mice; but whether and how these findings are pertinent to the inception of human cancer remain unknown. Here we show that SMURF2 is essential to protect human dermal fibroblasts (HDFs) from malignant transformation, and its depletion converts HDFs into tumorigenic entity. This phenomenon was associated with the radical changes in chromatin structural and epigenetic landscape, dysregulated gene expression and cell-cycle control, mesenchymal-to-epithelial transition and impaired DNA damage response. Furthermore, we show that SMURF2-mediated tumor suppression is interlinked with SMURF2's ability to regulate the expression of two central chromatin modifiers-an E3 ubiquitin ligase RNF20 and histone methyltransferase EZH2. Silencing these factors significantly reduced the growth and transformation capabilities of SMURF2-depleted cells. Finally, we demonstrate that SMURF2-compromised HDFs are highly tumorigenic in nude mice. These findings suggest the critical role that SMURF2 plays in preventing malignant alterations, chromosomal instability and cancer.

Placental pathologies associated with intra-uterine fetal growth restriction complicated with and without oligohydramnios.

PURPOSE: To compare the placental pathologies and perinatal outcomes in fetal growth restriction (FGR) pregnancies with and without oligohydramnios. METHODS: A retrospective cohort study, comparing placental findings in all singleton deliveries with FGR. RESULTS: Macroscopic placental findings were available for 1,104 singleton FGR pregnancies. A total of 397 placentas were microscopically examined; of which 89 placentas were of FGR neonates who had oligohydramnios. No significant differences in placental vascular mal-perfusion were found between pregnancies with and without oligohydramnios (69.3 vs. 74.3%; P = 0.357). Likewise, no significant differences were noted between the groups regarding diffuse villous fibrosis (10.1 vs. 4.9%; P = 0.573), and amnion cell metaplasia (65.9 vs. 64.3%; P = 0.779). Cases of FGR complicated with oligohydramnios had significantly higher rates of perinatal mortality (9.9 vs. 5.9%; P = 0.028), preterm deliveries (34.9 +/- 3.4 vs. 35.4 +/- 3.1 weeks of pregnancy; P = 0.041), and lower birth weight (1,737 +/- 542 vs. 1,845 +/- 467 g; P = 0.002) compared to FGR without oligohydramnios. CONCLUSIONS: Oligohydramnios is a significant risk factor for adverse perinatal outcome in FGR pregnancies; nevertheless, no significant differences in placental pathologies were noted.

Splenic metastasis from endometrial carcinoma: report of a case and review of literature.

INTRODUCTION: Splenic metastasis from endometrial carcinoma is a rare clinical event, with only 11 cases documented previously in the literature. CASE REPORT: A 58-year-old woman had surgery and radiotherapy for stage IIB endometrial carcinoma. Eighteen months later, PET scan discovered a hypermetabolic splenic mass and two hypermetabolic lung nodules. Spleen biopsy showed metastasis from endometrial carcinoma. Chemotherapy with six cycles of cyclophosphamide, adriamycin and cisplatin effected a partial response of the splenic and lung metastasis. After few months, however, splenectomy was performed because of substantial growth of the spelnic metastasis and it confirmed that the splenic metastasis was of endometrial origin and solitary in the peritoneal cavity. After splenectomy, the patient received chemotherapy with six cycles of paclitaxel. To date, 6 months after splenectomy, she is alive with no intraperitoneal disease and with few stable lung metastases. CONCLUSION: This is the 12th reported case of splenic metastasis from endometrial carcinoma. Splenic metastasis from endometrial carcinoma is usually solitary splenic metastasis limited to the splenic parenchyma. Splenectomy is an appropriate treatment to avoid splenic rupture, splenic vein thrombosis and painful splenomegaly, to circumvent the splenic metastasis being a source of secondary metastatic disease, and to provide the potential for cure or extended survival. Since patients with splenic metastasis may be asymptomatic and the interval between the diagnoses of endometrial carcinoma and splenic metastasis may be prolonged, careful and extended follow-up after primary treatment of endometrial carcinoma is warranted.

Altered Expression and Localization of Tumor Suppressive E3 Ubiquitin Ligase SMURF2 in Human Prostate and Breast Cancer.

SMURF2, an E3 ubiquitin ligase and suggested tumor suppressor, operates in normal cells to prevent genomic instability and carcinogenesis. However, the mechanisms underlying SMURF2 inactivation in human malignancies remain elusive, as SMURF2 is rarely found mutated or deleted in cancers. We hypothesized that SMURF2 might have a distinct molecular biodistribution in cancer versus normal cells and tissues. The expression and localization of SMURF2 were analyzed in 666 human normal and cancer tissues, with primary focus on prostate and breast tumors. These investigations were accompanied by SMURF2 gene expression analyses, subcellular fractionation and biochemical studies, including SMURF2's interactome analysis. We found that while in normal cells and tissues SMURF2 has a predominantly nuclear localization, in prostate and aggressive breast carcinomas SMURF2 shows a significantly increased cytoplasmic sequestration, associated with the disease progression. Mechanistic studies showed that the nuclear export machinery was not involved in cytoplasmic accumulation of SMURF2, while uncovered that its stability is markedly increased in the cytoplasmic compartment. Subsequent interactome analyses pointed to 14-3-3s as SMURF2 interactors, which could potentially affect its localization. These findings link the distorted expression of SMURF2 to human carcinogenesis and suggest the alterations in SMURF2 localization as a potential mechanism obliterating its tumor suppressor activities.

Smurf2 regulates stability and the autophagic-lysosomal turnover of lamin A and its disease-associated form progerin.

A-lamins, encoded by the LMNA gene, are major structural components of the nuclear lamina coordinating essential cellular processes. Mutations in the LMNA gene and/or alterations in its expression levels have been linked to a distinct subset of human disorders, collectively known as laminopathies, and to cancer. Mechanisms regulating A-lamins are mostly obscure. Here, we identified E3 ubiquitin ligase Smurf2 as a physiological regulator of lamin A and its disease-associated mutant form progerin (LAΔ50), whose expression underlies the development of Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging syndrome. We show that Smurf2 directly binds, ubiquitinates, and negatively regulates the expression of lamin A and progerin in Smurf2 dose- and E3 ligase-dependent manners. Overexpression of catalytically active Smurf2 promotes the autophagic-lysosomal breakdown of lamin A and progerin, whereas Smurf2 depletion increases lamin A levels. Remarkably, acute overexpression of Smurf2 in progeria fibroblasts was able to significantly reduce the nuclear deformability. Furthermore, we demonstrate that the reciprocal relationship between Smurf2 and A-lamins is preserved in different types of mouse and human normal and cancer tissues. These findings establish Smurf2 as an essential regulator of lamin A and progerin and lay a foundation for evaluating the efficiency of progerin clearance by Smurf2 in HGPS, and targeting of the Smurf2-lamin A axis in age-related diseases such as cancer.

Smurf2-Mediated Stabilization of DNA Topoisomerase IIα Controls Genomic Integrity.

DNA topoisomerase IIα (Topo IIα) ensures genomic integrity and unaltered chromosome inheritance and serves as a major target of several anticancer drugs. Topo IIα function is well understood, but how its expression is regulated remains unclear. Here, we identify the E3 ubiquitin ligase Smurf2 as a physiologic regulator of Topo IIα levels. Smurf2 physically interacted with Topo IIα and modified its ubiquitination status to protect Topo IIα from the proteasomal degradation in dose- and catalytically dependent manners. Smurf2-depleted cells exhibited a reduced ability to resolve DNA catenanes and pathological chromatin bridges formed during mitosis, a trait of Topo IIα-deficient cells and a hallmark of chromosome instability. Introducing Topo IIα into Smurf2-depleted cells rescued this phenomenon. Smurf2 was a determinant of Topo IIα protein levels in normal and cancer cells and tissues, and its levels affected cell sensitivity to the Topo II-targeting drug etoposide. Our results identified Smurf2 as an essential regulator of Topo IIα, providing novel insights into its control and into the suggested tumor-suppressor functions of Smurf2. Cancer Res; 77(16); 4217-27. ©2017 AACR.

Microfibrillar collagen hemostat-induced necrotizing granulomatous inflammation developing after craniotomy: a pediatric case series.

OBJECT: Microfibrillar collagen hemostat (MCH; trade name Avitene) is a partially water-insoluble acid salt of purified bovine corium collagen. This agent has been widely used to control hemorrhage at surgery, and especially during pediatric neurosurgeries at the authors' institution. Despite its effectiveness, rare case reports detailing adverse inflammatory reactions to MCH have been documented. Based primarily on MR imaging, postoperative reactions have most commonly elicited clinical differential diagnoses of tumor recurrence or abscess. According to the literature, MCH induces a very characteristic mixed inflammatory response that is rich in eosinophils; in light of these observations, many authors have suggested an allergy-based pathogenesis. METHODS: The authors retrospectively reviewed 3 pediatric neurosurgical cases treated at their institution, wherein a common histomorphological inflammatory reaction to MCH was elicited at the site of prior craniotomy. RESULTS: Case 1 is that of a 10-year-old girl whose diagnosis was a right temporal lobe ganglioglioma, classified as WHO Grade I. Case 2 is that of a 9-year-old boy whose diagnosis was a left parietal lobe anaplastic ependymoma, classified as WHO Grade III. Finally, Case 3 is that of a 15-year-old girl whose diagnosis was focal cortical dysplasia Type IIA affecting the left occipital lobe. Each patient presented with new or recurrent seizures 5­6 weeks after the initial resection. The postsurgical reactions incited by MCH mimicked the radiological appearance of either an abscess (Cases 2 and 3) or recurrent tumor (Case 1). Histologically, the mixed inflammatory infiltrate was typified by the presence of MCH-centric necrotizing granulomas that were surrounded by a palisade of macrophages and often several eosinophils. CONCLUSIONS: The findings are in keeping with previous case reports describing the clinicopathological features of adverse reactions occurring due to MCH. Based on the authors' observations, the possibility of an idiopathic inflammatory reaction to MCH should be considered when either seizures, a typical radiological appearance (that is, consistent with tumor recurrence or abscess formation), or both arise shortly after initial surgery. A conservative treatment approach to this type of inflammatory lesion appears to be the most appropriate management strategy.

A piece in the puzzle of intrauterine fetal death: pathological findings in placentas from term and preterm intrauterine fetal death pregnancies.

OBJECTIVE: To compare pathological findings of placentas from term and preterm pregnancies complicated by intrauterine fetal death (IUFD). STUDY DESIGN: A retrospective cohort study was conducted including deliveries complicated by IUFD. A comparison was made between placentas from term and preterm (<37 weeks' gestation) pregnancies complicated by IUFD. A second analysis was undertaken comparing IUFD placentas delivered before and after 34 weeks' gestation. Uteroplacental insufficiency was defined when one or more of the following pathological features were found: placental infarct, poor vascularity of the chorionic villi, intravascular thrombi and vascular occlusion. RESULTS: During the study period, 849 placentas of IUFD were examined. Gross and microscopic pathological finding were noted. When comparing gross and microscopic findings in term and preterm (<37 weeks) IUFD placentas, higher rates of calcifications, tissue congestion and cellular metaplasia were found in term vs. preterm placentas. Significantly increased rates of poor tissue vascularity, placental vascular occlusion and uteroplacental insufficiency were demonstrated in preterm IUFD placentas. When comparing pathological findings in IUFD placentas delivered before and after 34 weeks' gestation, higher rates of abnormal cord insertion, calcifications, tissue congestion, infarcts and intravascular thrombi as well as poor tissue vascularity and placental vascular occlusion were demonstrated in IUFD placentas delivered before 34 weeks. Regardless of gestational age at the time of IUFD in more than 90% of placentas vascular wall thickening was found. A third of both term and preterm placentas demonstrated histological chorioamionitis. CONCLUSIONS: A vast majority of IUFD placentas reveal numerous pathological findings that reflect uteroplacental insufficiency and abnormal blood supply. Different characteristics were noted in term and preterm placentas of pregnancies complicated by IUFD. Better definition of causes and associated placental pathological findings of IUFD might aid clinicians in counseling such patients regarding the reason and risk of recurrence in subsequent pregnancies.