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Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl-/H+ exchanger, CLCN7 (ClC-7), encoded by CLCN7. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and -genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in Xenopus oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function CLCN7 variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.

In this case series, we demonstrate that Ursodeoxycholic acid (UDCA) improves liver dysfunction in Niemann-Pick type C (NPC) and may restore a suppressed cytochrome p450 system. NPC disease is a progressive neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 genes. Liver disease is a common feature presenting either acutely as cholestatic jaundice in the neonatal period, or in later life as elevated liver enzymes indicative of liver dysfunction. Recently, an imbalance in bile acid synthesis in a mouse model of NPC disease was linked to suppression of the P450 detoxification system and was corrected by UDCA treatment. UDCA (3α, 7β-dihydroxy-5β-cholanic acid), a hydrophilic bile acid, is used to treat various cholestatic disorders. In this report we summarise the findings from four independent cases of NPC, three with abnormal liver enzyme levels at baseline, that were subsequently treated with UDCA. The patients differed in age and clinical features, they all tolerated the drug well, and in those with abnormal liver function, there were significant improvements in their liver enzyme parameters.

Primary ovarian melanoma arising on a mature ovarian cystic teratoma is extremely rare. As best of our knowledge, to date, 49 cases have been reported in literature. Few information was reported about best management and therapy. We present a case occurred in a 69-year-old woman, without symptoms, who come to our unit for stress incontinence. A pelvic mass was detected and, after imaging evaluation, surgery was performed. The diagnosis was ovarian melanoma arose on a mature teratoma. No other adjuvant treatment was proposed after surgery. She died 9 months after the first diagnosis. Primary ovarian melanoma is a definite entity associated with a variable natural history and poor prognosis. Differential diagnosis is a challenge for the pathologist, because it must be differentiated by metastatic melanoma. The corner stone treatment of this disease is surgery; however, chemotherapy, immunotherapy, and target therapy seem to have a role.

Introduction Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterised by partial oculocutaneous albinism, a bleeding diathesis, immunological dysfunction and neurological impairment. Bi-allelic loss-of-function variants in LYST cause CHS. LYST encodes the lysosomal trafficking regulator, a highly conserved 429 kDa cytoplasmic protein with an unknown function. Methods: To further our understanding of the pathogenesis of CHS, we conducted clinical evaluations on individuals with CHS enrolled in our natural history study. Using genomic DNA Sanger sequencing, we identified novel pathogenic LYST variants. Additionally, we performed an extensive literature review to curate reported LYST variants and classified these novel and reported variants according to the American College of Medical Genetics/Association for Molecular Pathology variant interpretation guidelines. Results Our investigation unveiled 11 novel pathogenic LYST variants in eight patients with a clinical diagnosis of CHS, substantiated by the presence of pathognomonic giant intracellular granules. From these novel variants, together with a comprehensive review of the literature, we compiled a total of 147 variants in LYST, including 61 frameshift variants (41%), 44 nonsense variants (30%), 23 missense variants (16%), 13 splice site variants or small genomic deletions for which the coding effect is unknown (9%), 5 in-frame variants (3%) and 1 start-loss variant (1%). Notably, a genotype-phenotype correlation emerged, whereby individuals harbouring at least one missense or in-frame variant generally resulted in milder disease, while those with two nonsense or frameshift variants generally had more severe disease. Conclusion The identification of novel pathogenic LYST variants and improvements in variant classification will provide earlier diagnoses and improved care to individuals with CHS. [ABSTRACT FROM AUTHOR]

We reported a case of secondary abdominal pregnancy with placental implantation into the fallopian tube, diagnosed at 16 weeks, in a woman admitted to the emergency room complaining of syncopal attacks. The best approach would be termination of the pregnancy, taking into consideration the high risk to the mother and the low possibility of alive and healthy birth. We had to perform an urgent surgical intervention due to the fact that the patient was in a clinically unstable condition, which was related to hemoperitoneum. If placental implantation is on abdominal organs or vessel the best approach would be to ligate the cord and to leave placenta in situ. Taking into consideration the place of placental implant, the removal of the fallopian tube with the placenta was the safest approach in this case. The best and most acceptable form of treatment would be individualized in case of rare form of ectopic pregnancy.

Uterus didelphys accounts for 13% of uterine anomalies and has been correlated with preterm delivery and fetal malpresentation at delivery. A 37-year-old pregnant woman reported a spontaneous pregnancy in the right horn of a uterus didelphys. The course of the pregnancy was complicated by gestational diabetes, but no miscarriage threat or preterm delivery threat was reported during this pregnancy. She arrived at our division, in labor, at 39.2 gestational weeks'. She delivered by cesarean section due to failure to progress at 5 cm. Her post-operative course was uneventful. Vaginal delivery could be a safe option and the induction of labor or the use of oxytocin could be helpful in such cases, but recommended doses and labor time should be evaluated, so cesarean section is to date the most frequent delivery route in uterus didelphys at term. [ABSTRACT FROM AUTHOR]

Background and Objectives: Data on contrast-enhanced endoscopic ultrasound (CE-EUS) for colorectal cancer (CRC) evaluation are scarce. Therefore, we aimed to assess the vascular perfusion pattern in CRC by quantitative CE-EUS and compare it to immunohistochemical and genetic markers of angiogenesis., Patients and Methods: We performed a retrospective analysis of CE-EUS examinations of 42 CRC patients, before any therapy. CE-EUS movies were processed using a dedicated software. Ten parameters were automatically generated from the time-intensity curve (TIC) analysis: peak enhancement (PE), rise time (RT), mean transit time, time to peak (TTP), wash-in area under the curve (WiAUC), wash-in rate (WiR), wash-in perfusion index (WiPI), wash-out AUC (WoAUC), and wash-in and wash-out AUC (WiWoAUC). The expression levels of the vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2 genes were assessed from biopsy samples harvested during colonoscopy. Microvascular density and vascular area were calculated after CD31 and CD105 immunostaining., Results: Forty-two CE-EUS video sequences were analyzed. We found positive correlations between the parameters PE, WiAUC, WiR, WiPI, WoAUC, WiWoAUC, and N staging (Spearman r = 0.437, r = 0.336, r = 0.462, r = 0.437, r = 0.358, and r = 0.378, respectively, P < 0.05), and also between RT and TTP and CD31 vascular area (r = 0.415, and r = 0.421, respectively, P < 0.05). VEGFR1 and VEGFR2 expression did not correlate with any of the TIC parameters., Conclusions: CE-EUS with TIC analysis enables minimally invasive assessment of CRC angiogenesis and may provide information regarding the lymph nodes invasion. However, further studies are needed for defining its role in the evaluation of CRC patients., Competing Interests: There are no conflicts of interest

Colorectal cancer (CRC) remains a leading cause of cancer death in both men and women worldwide. Among the factors and mechanisms that are involved in the multifactorial etiology of CRC, autophagy is an important transformational switch that occurs when a cell shifts from normal to malignant. In recent years, multiple hypotheses have been considered regarding the autophagy mechanisms that are involved in cancer. The currently accepted hypothesis is that autophagy has dual and contradictory roles in carcinogenesis, but the precise mechanisms leading to autophagy in cancer are not yet fully defined and seem to be context dependent. Autophagy is a surveillance mechanism used by normal cells that protects them from the transformation to malignancy by removing damaged organelles and aggregated proteins and by reducing reactive oxygen species, mitochondrial abnormalities and DNA damage. However, autophagy also supports tumor formation by promoting access to nutrients that are critical to the metabolism and growth of tumor cells and by inhibiting cellular death and increasing drug resistance. Autophagy studies in CRC have focused on several molecules, mainly microtubule-associated protein 1 light chain 3, beclin 1, and autophagy related 5, with conflicting results. Beneficial effects were observed for some agents that modulate autophagy in CRC either alone or, more often, in combination with other agents. More extensive studies are needed in the future to clarify the roles of autophagy-related genes and modulators in colorectal carcinogenesis, and to develop potential beneficial agents for the prognosis and treatment of CRC.