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Hartsfield syndrome (HS) is an ultrarare developmental disorder mainly featuring holoprosencephaly and ectrodactyly. It is caused by heterozygous or biallelic variants in FGFR1. Recently, a dominant-negative effect was suggested for FGFR1 variants associated with HS. Here, exome sequencing analysis in a 12-year-old boy with HS disclosed a novel de novo heterozygous variant c.1934C>T in FGFR1 predicted to cause the p.(Ala645Val) amino-acid substitution. In order to evaluate whether the variant, changing a highly conserved residue of the kinase domain, affects FGFR1 function, biochemical studies were employed. We measured the FGFR1 receptor activity in FGF2-treated cell lines exogenously expressing wild-type or Ala645Val FGFR1 by monitoring the activation status of FGF2/FGFR1 downstream pathways. Our analysis highlighted that RAS/ERK1/2 signaling was significantly perturbed in cells expressing mutated FGFR1, in comparison with control cells. We also provided preliminary evidence showing a modulation of the autophagic process in cells expressing mutated FGFR1. This study expands the FGFR1 mutational spectrum associated with HS, provides functional evidence further supporting a dominant-negative effect of this category of FGFR1 variants and offers initial insights on dysregulation of autophagy in HS.

Cerebral cavernous malformation (CCM) is a capillary malformation arising in the central nervous system. CCM may occur sporadically or cluster in families with autosomal dominant transmission, incomplete penetrance, and variable expressivity. Three genes are associated with CCM KRIT1, CCM2, and PDCD10. This work is a retrospective single-center molecular study on samples from multiple Italian clinical providers. From a pool of 317 CCM index patients, we found germline variants in either of the three genes in 80 (25.2%) probands, for a total of 55 different variants. In available families, extended molecular analysis found segregation in 60 additional subjects, for a total of 140 mutated individuals. From the 55 variants, 39 occurred in KRIT1 (20 novel), 8 in CCM2 (4 novel), and 8 in PDCD10 (4 novel). Effects of the three novel KRIT1 missense variants were characterized in silico. We also investigated a novel PDCD10 deletion spanning exon 4-10, on patient's fibroblasts, which showed significant reduction of interactions between KRIT1 and CCM2 encoded proteins and impaired autophagy process. This is the largest study in Italian CCM patients and expands the known mutational spectrum of KRIT1, CCM2, and PDCD10. Our approach highlights the relevance of seeking supporting information to pathogenicity of new variants for the improvement of management of CCM., (© 2018 Wiley Periodicals, Inc.)

Background and Purpose: The goal of this study was to compare the inter-observer variability between CT and MRI for the delineation of pharyngo-laryngeal SCC, parotid glands and spinal cord., Patients and Methods: Twenty pharyngo-laryngeal tumors were delineated by five observers on CT and MRI, using consistent delineation guidelines. Spinal cords and parotid glands were also delineated on CT and MRI by three observers. Mean GTVs and coefficients of variation were calculated for each observer and compared using ANOVA and its derived Pearson intra-class coefficient (R). For GTVs, a mismatch analysis (ratio between intersection and union volumes) was also performed., Results: Regarding oropharyngeal GTVs (n=10), no significant difference was observed between observers either with CT (33.9, 31.1, 32, 34 and 34.7 ml, five observers, P=0.47) or with MRI (30.5, 29.4, 30.1 and 31.5 ml, four observers, P=0.59). CVs (13.6 vs 12.9%), (0.98 vs 0.99) and mismatches (0.43 vs 0.42) between CT and MRI did not significantly differ. Regarding laryngeal-hypopharyngeal GTVs (n=10), no significant difference was observed between observers either on CT (18.1, 20.7, 20.9, 19.3 and 21.9 ml, five observers, P=0.29) or on MRI (19.3, 21.5, 20, 22.1 and 21.8 ml, five observers, P=0.16). CVs (20.2 vs 13.8%), (0.94 vs 0.94) and mismatches (0.31 vs 0.41) were comparable. Regarding OARs, a small but significant difference in mean parotid volume was observed between observers (P<0.001) and between modalities (P<0.001) (CT: 34.8, 29.4, and 26.8 ml; MRI: 30.6, 27.9 and 20.4 ml). Similar results were obtained for mean spinal cord volumes (CT: 10.7, 10.6, and 9.5 ml; MRI: 8.7, 8.5 and 8.2 ml; P=0.05).

Background: The optimal treatment for locoregionally recurrent rectal cancer after curative surgery has not yet been defined. The definition of prognostic factors could lead to the selection of an aggressive therapeutic approach in patients with favourable prognosis alone., Patients and Methods: The records of thirty-nine ambulatory pts, 15 female and 24 male, with diagnosis of locoregionally recurrent rectal cancer (LRRC) after curative surgery and treated with radiotherapy were retrospectively analyzed. The following factors were analyzed for their ability to predict the clinical response and outcome for LRRC: age, sex, initial tumor grading, primary surgical approach, initial primary tumor stage according to Dukes' classification, disease free survival (time to primary surgery and detection of a LRRC), pelvic-perineal structure affected by recurrence, total radiation dose, chemotherapy with fluorouracil, symptomatic response to the therapy, locoregional symptomatic re-recurrence, systemic progression disease., Results: In the univariate analysis, predictive factors for survival, were graded (G1-2 vs G3 p = 0.04), Dukes' stage at first diagnosis (A-B vs C p = 0.01), and site of pelvic-perineal recurrence (Pelvic mass alone yes vs no p = 0.01; Nerve and/or Osseous involvement yes vs no p < 0.001). Following therapy for LRRC, a better survival was observed in pts with a complete symptomatic response (complete remission vs partial remission vs no change p < 0.001), without a further locoregional symptomatic re-recurrence (re-recurrence, yes vs no p = 0.001) and/or appearance of metastatic disease (yes vs no p < 0.001).

There are numerous clinical situations in which interventional angiography fully reveals its two-fold diagnostic and therapeutic value. The present review focuses attention on the use of such procedures in certain thoracic emergencies. Indications, diagnostic results and therapeutic advantages are examined together with possible complications. Pulmonary embolism is a serious circulatory condition that is often difficult to diagnose because of the lack of specificity of its accompanying symptoms. In these cases the role of the angiographic radiologist is often three-fold: diagnosis, therapy (possibility of carrying out locoregional thrombolysis), and prophylaxis (positioning of caval filters that prevent the migration of thrombi). Haemoptysis may arise from both the pulmonary and bronchial vessels and may be caused by various pathologies (cancer, angiodysplasia, vasculitis, aspergillosis). Angiographic study in such cases is indispensable for identifying the source of bleeding and for arresting, using embolising material, haemorrhage that it is no longer possible to control with other therapeutic modalities. Foreign bodies held in the vascular tree are in the main fragments of catheters detached accidentally or as a result of incorrect manoeuvres or for defects of construction of the material. Their removal is possible today by using, percutaneously, angiographic techniques (snare loop, basket, hook system, balloon catheters) which make it possible to hook up the fragment and remove it.

The frequency of peptic ulcer and the role of ulcerogenic risk factors in cirrhotic patients were evaluated in a retrospective study. Peptic disease was observed in 18.2% of the cirrhotic patients examined. When compared to the prevalence of ulcerative lesions in the general population, this finding suggests that cirrhotic patients have the same probability of being affected by peptic ulcer as non-cirrhotic subjects. The analysis of ulcerogenic risk factors highlighted the importance of alcohol and smoking. The etiology of cirrhosis and portal hypertension were not found to be important. In conclusion, peptic disease is not more frequent in cirrhotic patients than in the general population.

The multicellular spheroid model previously has been used to characterize secondary allograft responses in sensitized mice. In this study multicellular spheroids of EMT6 mammary sarcoma were implanted into unsensitized allogeneic mice to assess sensitization, graft infiltration, and functional activities of host cells in a primary allograft response. During the first 5 days after implantation, the spheroids continued to grow similar to controls maintained in vitro. After 6 days the spheroids decreased in size, and recovery of clonogenic tumor cells fell markedly. Cytotoxic effector cells active in an in vitro 51Cr release assay were recoverable from the spheroids beginning at day 4 and reached a maximum at day 7. Lymphocytes and macrophages were present in the largest numbers at days 7 to 8. The predominant cytotoxic cell appears to be a T lymphocyte.