Biallelic EPCAM deletions induce tissue-specific DNA repair deficiency and cancer predisposition.

We report a case of Mismatch Repair Deficiency (MMRD) caused by germline homozygous EPCAM deletion leading to tissue-specific loss of MSH2. Through the use of patient-derived cells and organoid technologies, we performed stepwise in vitro differentiation of colonic and brain organoids from reprogrammed EPCAMdel iPSC derived from patient fibroblasts. Differentiation of iPSC to epithelial-colonic organoids exhibited continuous increased EPCAM expression and hypermethylation of the MSH2 promoter. This was associated with loss of MSH2 expression, increased mutational burden, MMRD signatures and MS-indel accumulation, the hallmarks of MMRD. In contrast, maturation into brain organoids and examination of blood and fibroblasts failed to show similar processes, preserving MMR proficiency. The combined use of iPSC, organoid technologies and functional genomics analyses highlights the potential of cutting-edge cellular and molecular analysis techniques to define processes controlling tumorigenesis and uncovers a new paradigm of tissue-specific MMRD, which affects the clinical management of these patients.

Multiple oral and cerebral relapses of a Granular cell tumor (Abrikossoff Tumor) in a young girl affected by congenital dyserythropoietic anemia type II.

CASE REPORT: A 14-year-old girl presented with 1 cm large whitened lesion on the ventral surface of the tongue, appeared from 1 month. Past history showed congenital dyserythropoietic anemia type II. The lesion was excised and microscopic and immunohistochemical analyses were compatible with benign Abrikossoff tumor. Total body MRI was negative. After six months the patient presented a second tongue lesion and four months later another large painful lesion in the soft palate, with the same istological diagnosis. In addition, she had other multiple lesions: two apperead at pharyngeal level (not biopsied) that remain stable over time, and one at the pituitary gland. CONCLUSION: Granular cell tumors, with or without multiple lesions, are rare in children. About 50% of cases involve the head and neck region, with the tongue being the most affected site. Therapy is based on the surgical excision of the lesions; however some tumor forms, although their histological aspect of benignity, often have an important infiltrative power, making the therapeutic approach difficult, as in our case.

Extramedullary hematopoiesis in the facial sinus in a patient homozygous for Hemoglobin Lepore: the first case in literature.

Extramedullary hematopoiesis (EMH) is a proliferation of hematopoietic tissue outside the bone marrow. The most affected areas are paravertebral ones. We report the case of a patient with homozygous Hb Lepore, not regularly transfused since the age of four years until the age of 29 years, when paravertebral heterotopic masses were first observed. After about 10 years she started reporting clinical signs suggestive of sinusitis. Computed tomography (CT) and Magnetic Resonance Imaging (MRI) showed heterotopic masses in the ethmoid and in the frontal sinuses. Involvement of the sinuses of the large facial area represents a rare localization of EMH. Various cases have been reported in patients with thalassemia intermedia, but no case has been reported with HbLepore. The diagnostic gold standard is MRI, which provides highly accurate and clear images. The treatment is based on hydroxyurea and/or an intensive transfusional regime and sometimes on surgery.

Retinal vein occlusion in child with rare mutations in genes for thrombophilia.

INTRODUCTION: Retinal vein occlusions (RVOs) are rare in the younger population. Hematological pro-thrombotic factors are thought to be important in a minority, amplifying an atherosclerotic anatomical predisposition. CASE REPORT: Anotherwise healthy 13-year-old girl presented two episodes of sudden decreased vision in few months.Ophthalmological exams pointed out post-thrombotic intra-retinal hemorrhage. All investigations were normal, thrombophilia screen showed factor XII deficiency and genetic mutations of methylenetetrahydrofolate reductase (MTHFR), angiotesin convertin enzyme (ACE) and angiotensinogen (AGT). Two intravitreal injection of bevacizumab was administered with improving visual acuity; subsequently the patient did not report further episodes. DISCUSSION: In addition to traditional factors with procoagulant activity, factor XII deficiency plays an important role in thrombosis's mechanism. Its deficiency causes a marked prolongation of the activated partial thromboplastin time in the laboratory examination. Moreover also MTHFR, ACE and AGT could have been involved in this case, so it is important to evaluate these parameters in the differential diagnosis of RVOs.

Do you remember scurvy?

Scurvy, a disease caused by a deficiency of ascorbic acid (vitamin C), is not very common disease especially in pediatric age. In the late nineteenth century, instead, we assisted to increase incidence of this problem for the use of heated milk and convenience foods. We report two cases of scurvy: a child of 3 years old came to our observation for an important gums' stomatitis, fever, widespread petechiae and ecchymosis on the skin of the lower limbs; in the second moment he had pain in upper and lower limbs with difficulty in walking; a second child of 4 years came to our observation for pain lower limbs and maintained the posture of the legs down, inability to walking, with reduced muscle tone and trophism in all limbs; at the instrumental examination he had an alveolar hemorrhage. The two boys had a history of a diet completely lacking in fruits and vegetables; they were drinking almost only milk. They carried various laboratory and instrumental tests, in particular X-ray of lower limbs that showed "a thick sclerotic metaphyseal line with beak-like excrescences of tibiae and femur". The characteristic radiological appearance, the particular clinical aspects, the dietary history and the dosage of vitamin C, have led us to the diagnosis of scurvy. They started therapy with vitamin C and they had a progressive improvement in general condition.

A case of spontaneous gastric rupture in a 5 years girl.

We describe a case of spontaneous gastric rupture in a child of 5 years old. The patient reached us in a serious condition; the anamnesis was negative for traumatic events or gastrointestinal disorders. An abdominal X-ray and CT scan revealed free air and fluid in the abdominal cavity, leading to the diagnosis of gastro-intestinal perforation. Submitted to urgent surgery, a rupture of the posterior wall of the stomach was found that was treated with gastrectomy "à la demande". The surgery follow-up was regular. Morphological and immunohistochemical study showed some muscular abnormalities of the muscular gastric wall.

[Management of perforations as adverse events of ERCP plus ES. Personal experience]. / Trattamento degli eventi perforativi post-colangiopancreatografia retrograda con sfinterotomia endoscopica. Esperienza personale.

UNLABELLED: INTRODUCTION. ERCP has brought real progress in the study and treatment of pancreatic and biliary diseases, because of its ambivalence as diagnostic and therapeutic procedure. Among its complications, perforations occur in fewer than 1% of patients, but are associated with a mortality rate of 16% -18%. CASE REPORTS: CASE 1- F, 89 years old with obstructive jaundice by choledocholithiasis submitted to ERCP plus ES, during which occurs type II lesion; the partial removing of stones from choledochus during the procedure allow us to opt for a conservative treatment, with resolution on post-ERCP day 12. CASE 2- F, 53 years old with recurring cholangitis and post-cholecystectomy stenosis of choledochus already treated by stenting; for the occurrence of type I lesion during ERCP, the patient undergoes surgery in emergency with healing in postoperative day 23. CASE 3- M, 84 years old with lithiasic cholecystitis, obstructive jaundice, lung emphysema and ischemic heart disease; after percutaneous cholecystostomy in emergency, we attempt to ERCP with evidence of type I lesion. Because of comorbility, we opt for a conservative treatment, not resolving, and then proceed to surgery. Exitus for cardio-respiratory complications. CASE 4- M, 89 years old with obstructive jaundice; ERCP is suspended for respiratory complications and then a PTC is perform; during it we note a type IV lesion, which is treated conservatively with resignation in day 12. CASE 5- F, 68 years old with cholecystitis and choledocholithiasis; during ERCP plus SE a type II lesion occurs with worsening signs of acute abdomen. Because of clinical conditions and the impossibility of carrying out stones from choledochus by endoscopy, we opt for a surgical treatment in emergency. Exitus for respiratory complications. DISCUSSION: Because of the controversy exists on what should be the management of perforations as adverse events of ERCP plus ES (immediate surgery or conservative therapy), we can only hope an eclectic approach based on the anatomical and clinical peculiarity of each case.

Hot-flashes in breast cancer survivors: effectiveness of low-dosage fluoxetine. A pilot study.

Breast carcinoma survivors suffering from hot-flashes experience a negative impact on their quality of life. Antidepressants have recently been proven to be effective in these women, significantly reducing the vasomotor symptoms. With this in mind, a single-arm clinical trial low-dose regimen of Fluoxetine (10 mg/day for 4 weeks) was given to twenty symptomatic breast cancer patients. Among the 12 women evaluated at the end of treatment, a statistically significant reduction of the mean number of daily hot-flashes (-36.3%, p = 0.001) and hot-flashes score (-46.2%, p = 0.0006) had been detected as compared to the baseline data. Although the dosage of Fluoxetine used in these trials was lower than earlier published, it should be noted that these positive results were achieved without any relevant side effects.

Primary leiomyosarcoma of the fallopian tube: a case report.

A primary leiomyosarcoma (LMS) arising from the left fallopian tube in a perimenopausal 48-year-old woman is reported. Primary tubal LMS is an uncommon, exceedingly rare neoplasm, accounting for only a few reported cases so far. To our knowledge, the present case is the 17th tubal LMS reported in the English-language literature. The diagnosis is usually made at the time of laparotomy for a pelvic or adnexal mass or other gynaecological indications. As in ovarian neoplasms, the mainstay of treatment is represented by debulking surgery consisting of total abdominal hysterectomy, bilateral salpingo-oophorectomy, random biopsies, peritoneal washing and excision of all the abdominal tumour masses. Although the approach is radical, the clinical behaviour is very poor. The role of adjuvant radio- or chemotherapy still remains unsolved.

Final height in short polytransfused thalassemia major patients treated with recombinant growth hormone.

We measured the final height (FH) of 25 short polytransfused thalassemia major (Th) patients (18 males) with a reduced GH reserve treated for 3.3 +/- 1.2 yr with recombinant GH (rhGH), 0.2 mg/kg/week sc. At baseline, all patients were clinically prepubertal; their chronological (CA) and bone ages (BA) were 13.6 +/- 2.0 and 11.4 +/- 1.6 yr, respectively. In 9 out of 18 males and 5 out of 7 females, the onset of puberty occurred spontaneously during the treatment. At the end of the rhGH administration, the height of the enrolled children was not significantly increased when calculated for CA (HxCA), while it was significantly decreased (p=0.004) when calculated for BA (HxBA); the BA increase (3.29 +/- 1.65 yr) was significantly higher (p<0.001) than the height age increase (2.16 +/- 0.98 yr). The FHxCA showed a significant increase (p=0.001) compared to both baseline and the end of therapy, while the FHxBA was significantly decreased (p<0.001) compared with the corresponding value at baseline. At the end of therapy, both HxCA and HxBA resulted positively related to the BA at baseline (r=0.50 and 0.42, p=0.012 and 0.034, respectively). FH was positively correlated with CA (r=0.63, p=0.001), BA (r=0.68, p<0.001) and HxBA (r=0.59, p=0.002) evaluated at baseline, and with both HxCA and HxBA (r=0.82 and 0.74, respectively, p<0.001), evaluated at the end of treatment. A negative correlation was found between FH and the length of treatment (r=-0.56, p=0.004). Our data seem to exclude that prolonged rhGH therapy could improve FH in Th patients; on the contrary, a negative effect may be hypothesized.

Assessment of risk factors and human papillomavirus (HPV) related pathogenetic mechanisms of CIN in HIV-positive and HIV-negative women. Study design and baseline data of the HPV-PathogenISS study.

OBJECTIVES: In women with HIV-associated immunosuppression, HPV infections have an increased risk of progression to high-grade cervical intraepithelial neoplasia (CIN). With the HAART-induced prolonged survival and more protracted clinical course of AIDS, progression of CIN to cervical cancer (CC) has become a clinically relevant issue, and the mechanisms responsible for HIV-HPV interactions need further elucidation. The study design and analysis of the baseline data of our new project are presented. MATERIAL AND METHODS: This project is a combination of a prospective cohort study of HIV- and HIV+ women, and a retrospective analysis of CIN lesions and cervical cancer. Up to the present, 244 women have been enrolled (17 HIV+) and subjected to epidemiological interview, colposcopic examination, sampling for HPV testing and typing (PCR, InnoLiPA), and HPV serology. The retrospective series of biopsies were analysed for 13 biomarkers (monitoring key molecular events) using immunohistochemistry and tested for HPV by PCR and TaqMan. RESULTS: HIV- and HIV+ women differ in their exposure status to many of the key epidemiological risk factors of cervical cancer, the most significant ones being number of sexual partners (p = 0.0001), age at onset of sexual activity (p = 0.002), and contraception (yes-no) (p = 0.009). The differences in the baseline clinical observations are less dramatic; HIV-positive women had more frequent HSIL PAP tests (p = 0.040), CIN2 or higher in cervical biopsy (p = 0.049), and external genital warts (p = 0.019). The factors predicting intermediate endpoint markers of cervical cancer, i.e., HSIL PAP smear, ATZ2 in colposcopy, and high-grade CIN in biopsy were analysed in univariate and multivariate regression models. All factors significant in univariate analysis were entered in the multivariate model; HIV-status and Pap smear history maintained their independent predictive power of the HSIL Pap test. The most powerful predictor of ATZ2 colposcopy was HSIL in Pap test. Only the HSIL Pap test and ATZ2 colposcopy remained significant independent predictors of high-grade CIN (p = 0.0001 and p = 0.008, respectively) in the multivariate model. CONCLUSIONS: The three intermediate endpoint markers are closely interrelated, but predicted in part by different covariantes in the causal pathway to cervical cancer. To elucidate whether the increased risk of HIV-positive women to high-grade CIN is due a) to their different exposure status to the risk factors, b) to the direct effects of HIV, or c) to molecular interactions between HIV and HPV, we need to complete these analyses separately in HIV+ and HIV- women.

Analysis of chromosomes 3, 7, X and the EGFR gene in uterine cervical cancer progression.

The aim of this study was to investigate the possible role of genetic alterations in the genesis and progression of cervical carcinomas. We analysed the 3, 7, X aneusomy of chromosomes and the status of the epidermal growth factor receptor (EGFR) gene by fluorescence in situ hybridisation (FISH) analysis. Polysomy of chromosomes 3 and X defined the transition from high-grade squamous intraepithelium lesions (HSIL) to cervical carcinoma. Chromosome 7 monosomy and polysomy did not show any statistical significant differences between the groups examined. When we compared the chromosomal aneusomies in all of the specimens using the Kruskal-Wallis test, significant differences (P = 0.0001, P = 0.0001 for chromosomes 3 and X, respectively) were observed. Using a ratio of the EGFR gene signals and chromosome 7 centromeric signals, no samples showed gene amplification. Our results demonstrate the importance of chromosomal 3 and X aneusomies in the development and progression from HSIL to cervical carcinoma, highlighting their usefulness as genetic markers for identifying SILs at high-risk of progression.

Inability of immunohistochemistry to predict clinical outcomes of endometrial cancer patients.

INTRODUCTION: Despite optimal surgery, some patients with early endometrial carcinoma develop recurrence and die of disease. A number of immunohistochemical (IHC)-identified cell products (markers) have been proposed as predictors of recurrence. This study characterizes a large series of endometrial carcinomas with previously described markers as well as markers that have not been investigated in endometrial carcinoma. PATIENTS AND METHODS: Women who had undergone surgery for endometrial carcinoma were identified and specimens accessed. Tissue blocks were evaluated for ten IHC markers. Results were correlated with last known clinical status. RESULTS: Mean follow-up was 43 months; complete data were available on 117 patients. Two women died of other causes; of the remaining 115, eight died of disease and six were alive with recurrence at last follow-up (12%). Vascular endothelial growth factor staining independently predicted recurrence and death. However, in multivariate analyses, only FIGO stage predicted outcome. DISCUSSION: Our goal was to identify markers to predict which women with endometrial carcinoma were likely to have disease recurrence. We evaluated cell-cycle regulatory proteins, growth factors, hormone receptors, and angiogenic factors, but did not identify any marker that independently predicted outcome in multivariate analysis. This may reflect the few negative outcomes in our population.

Growth and puberty in thalassemia major.

Present transfusional regimen protocols increase the life expectancy of patients with beta-thalassemia major, but cause a progressive iron overload that can be prevented or limited only by appropriate iron chelation. Siderosis is responsible for the clinical complications of the disease. Short stature and hypogonadism are extremely frequent in patients with thalassemia. Many factors are responsible for short stature in patients with thalassemia, the most important of which are dysfunction of the GH-IGF-I axis and desferoxamine (DFX)-induced bone dysplasia. Hypogonadism is the most frequent endocrine complication, mostly due to gonadotrophins deficiency secondary to iron overload. Sex steroid treatment for induction of puberty and/or maintenance of sexual characteristics is necessary. Both short stature and hypogonadism are present in a significant percentage of bone marrow transplanted patients with thalassemia. Factors responsible for short stature are previous iron overload, liver impairment, DFX treatment, and toxicity of chemotherapeutic agents. In some patients absence of pubertal development is due to gonadotropin insufficiency, probably secondary to previous iron overload; other patients exhibit hypergonadotrophic hypogonadism due to the toxic effect of chemotherapeutic agents on the gonads. Both groups need hormonal replacement therapy. These data support the need for vigilant follow-up of patients with thalassemia before and after transplantation, in order to treat endocrine dysfunctions at the appropriate age.

[Chest pain in adolescents]. / Il dolore toracico nell'adolescente.

In children and in adolescents, chest pain is relatively common and self-limiting. The close association between chest pain, cardiopathies and sudden death is the cause of intense anxiety in boys and their parents and even doctors. The most frequent causes of chest pain, the diagnosis and the eventual treatment are examined. Finally, the causes of chest pain due to drug abuse (in particular cocaine) and to CO poisoning are also examined. Good knowledge of the problem, an accurate anamnesis and a careful objective exam are useful to choose the most suitable treatment.