Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition.

The inflammasome is hypothesized to be a key mediator of the response to physiological and psychological stressors, and its dysregulation may be implicated in major depressive disorder. Inflammasome activation causes the maturation of caspase-1 and activation of interleukin (IL)-1ß and IL-18, two proinflammatory cytokines involved in neuroimmunomodulation, neuroinflammation and neurodegeneration. In this study, C57BL/6 mice with genetic deficiency or pharmacological inhibition of caspase-1 were screened for anxiety- and depressive-like behaviors, and locomotion at baseline and after chronic stress. We found that genetic deficiency of caspase-1 decreased depressive- and anxiety-like behaviors, and conversely increased locomotor activity and skills. Caspase-1 deficiency also prevented the exacerbation of depressive-like behaviors following chronic stress. Furthermore, pharmacological caspase-1 antagonism with minocycline ameliorated stress-induced depressive-like behavior in wild-type mice. Interestingly, chronic stress or pharmacological inhibition of caspase-1 per se altered the fecal microbiome in a very similar manner. When stressed mice were treated with minocycline, the observed gut microbiota changes included increase in relative abundance of Akkermansia spp. and Blautia spp., which are compatible with beneficial effects of attenuated inflammation and rebalance of gut microbiota, respectively, and the increment in Lachnospiracea abundance was consistent with microbiota changes of caspase-1 deficiency. Our results suggest that the protective effect of caspase-1 inhibition involves the modulation of the relationship between stress and gut microbiota composition, and establishes the basis for a gut microbiota-inflammasome-brain axis, whereby the gut microbiota via inflammasome signaling modulate pathways that will alter brain function, and affect depressive- and anxiety-like behaviors. Our data also suggest that further elucidation of the gut microbiota-inflammasome-brain axis may offer novel therapeutic targets for psychiatric disorders.

Malignant ovarian germ cell tumors in pediatric patients: The AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) study.

OBJECTIVE: Malignant ovarian germ cell tumors (MOGCT) carry an excellent prognosis, and the treatment aims to achieve results with the least possible treatment-related morbidity. The aim of this study was to assess the outcomes of pediatric patients with MOGCT. METHODS: Patients were treated according to their stage: surgery and surveillance for stage I; a modified bleomycin-etoposide-cisplatin (BEP) regimen for stages II (three cycles), III, and IV (three cycles) with surgery on residual disease. RESULTS: Seventy-seven patients were enrolled (median age 11.8 years), 26 with dysgerminoma (Dysg), 13 with immature teratoma and elevated serum alpha-fetoprotein levels (IT + AFP), and 38 with nondysgeminoma (Non-Dysg) staged as follows: 27 stage I, 13 stage II, 32 stage III, 5 stage IV. Among evaluable patients in stage I (5-year event-free survival [EFS] 72.1% [95% CI: 56.4-92.1%]; 5-year overall survival [OS] 100%), seven relapsed (three patients with Dysg and four patients with Non-Dysg) and were rescued with chemotherapy (plus surgery in three patients). Among the evaluable patients with stages II-IV, 48 (98%) achieved complete remission after chemotherapy ± surgery, one (IT + AFP, stage IV) had progressive disease. In the whole series (median follow-up 80 months), the 5-year OS and EFS were 98.5% (95% CI: 95.6-100%) and 84.5% (95% CI: 76.5-93.5%). CONCLUSIONS: We confirm the excellent outcome for MOGCT. Robust data are lacking on surgical staging, surveillance for Non-Dysg with stage I, the management of IT + AFP, and the most appropriate BEP regimen. As pediatric oncologists, we support the role of surveillance after proper surgical staging providing cases are managed by experts at specialized pediatric centers.

Surgical management of papillary thyroid carcinoma in childhood and adolescence: an Italian multicenter study on 250 patients.

PURPOSE: The extent of surgery for pediatric papillary thyroid carcinoma is debatable. The aim of this study was to evaluate the feasibility of offering pediatric patients a tailored surgical approach based on certain clinical features. METHODS: A national multicenter retrospective review of 250 pediatric patients treated for papillary thyroid carcinoma in a 14-year period was performed. Outcomes of interest included tumor-related features, type of surgery, surgical morbidity, disease-free and overall survival rates. Recurrence was thoroughly analyzed with particular focus on how it correlated with certain patient- and tumor-related features. RESULTS: The majority of patients (58.8 %) had tumors >2 cm in size. Nodal involvement occurred in 115/250 (46 %) patients and distant metastasis in 4 % (10/250). Total thyroidectomy and lobectomy were performed in 90.4 % (226/250) and 9.6 % (24/250) of patients, respectively. The overall rate of surgical complications was 20.8 % (52/250). These included transient and permanent hypoparathyroidism (13.6 and 4.4 %, respectively), and vocal fold palsy (2.8 %). All surgical complications occurred exclusively in the total thyroidectomy group. The rate of recurrent disease was 12 % (30/250) with the vast majority of recurrences (96.6 %) occurring in the total thyroidectomy group. The risk of recurrence correlated significantly with certain tumor-related features (size > 2 cm, multifocality, extrathyroidal invasion, nodal positivity, and distant metastasis). However, it did not correlate with the patient's age or sex. Overall survival was 100 %. CONCLUSION: Pediatric patients are likely to benefit from a tailored surgical strategy. Uniformly offering patients total thyroidectomy seems to be an overly radical approach.

Association between gastroesophageal reflux and endobronchial carcinoid: a case report.

Children with neurological disorders may suffer from gastroesophageal reflux disease (GERD). Typical symptoms are vomiting, regurgitation and hematemesis. Patients present with respiratory symptoms only in cases with swallowing disorders causing chronic airway aspiration. We report the case of a patient affected by chromosome 8 p deletion syndrome with mental retardation, referred to our unit for suspected GERD. Chest X-ray, performed at admission for coexisting respiratory complaints, showed left lower lobe pneumonia; esophageal pH monitoring and upper endoscopy were normal for GERD. To rule out chronic airway aspiration, gastroesophageal 99 mTc scintigraphy with lung scan 18 to 24 h after a test meal and video fluoroscopy swallowing study were performed, both negative. Two months later, a second episode of left lower lobe pneumonia occurred. A chest CT scan was performed and showed an endobronchial mass; the biopsy taken during the broncoscopy was not conclusive. Surgical excision resulted in a diagnosis of pulmonary carcinoid. Bronchial carcinoids, although rare, should be taken into consideration as a potential cause of recurrent pneumonia even in the presence of demonstrated GERD where severe respiratory infections only occur with coexisting chronic pulmonary aspiration, even in neurologically impaired people.

Unilateral vasectomy for intractable epididiymo-orchitis in patients with anorectal malformation.

BACKGROUND: Male patients treated for anorectal malformations (ARM) and recto-urethral fistula (RUF) tend to develop recurrent epididymo-orchitis (EO) which occurs approximately in 20% of all them. The optimal management of this condition is unclear because of the extreme its rarity and the unavailability of detailed analysis in literature. To date the majority of this patients benefits from medical treatment and symptoms reduce over time but few data have been published in literature about management of patients with intractable EO. OBJECTIVE: To describe the efficacy of unilateral vasectomy in patients operated on for anorectal malformations with RUF and affected by intractable EO. STUDY DESIGN: We present five patients who met the criteria for intractable EO, and followed at our centre four of whom have undergone unilateral vasectomy. RESULTS: The first episode of EO presented at 42,00 mos ±29.39. Initially, patients were all managed with analgesics and antibiotics. For the failure of therapy, five patients were all offered unilateral vasectomy but only four families accepted procedure. Surgical treatment was performed as a day case without complications. Postoperative follow up was 88,50 mos ±68.36. Prompt and durable resolution of symptoms was observed. DISCUSSION: The long-term effects of recurrent EO in ARM are often underestimated. Prompt and appropriate intervention should prevent this undesirable sequela. Unfortunately, the optimal management of this complication is unclear, partly because of its extreme rarity. The established management needs to follow the route of correcting underlying anomalies and providing long-term analgesic and antibiotics but this may have undesired side effects. We therefore offered families vasectomy for complete symptom resolution and/or drug withdrawal. Vasectomy, as a form of treatment for, can be justified if it can prevent pain, infection and destruction of the testes. Early vasectomy may save enough functional testis tissue. CONCLUSION: To date, the only available treatment to achieve definitive resolution of symptoms in intractable unilateral EO is vasectomy. Long-term effects of such procedure on fertility are unknown. The treatment of recurrent EO in cases without site predilection remains a matter of contention.

Minimally-invasive surgery in paediatric oncology: proposal of recommendations.

The Authors report a proposal of recommendations concerning Minimally Invasive Surgery (MIS) in Paediatric Oncology. Since the exact role of MIS in Paediatric Oncology is still not completely defined, a restrict panel of Italian Paediatric Surgeons, some interested in Oncologic Surgery, others in MIS, prepared a schematic document, mainly founded on literature data, to provide Paediatric Surgeons with recommendations useful to approach paediatric tumours with MIS. The final draft was approved by the Italian Group of Paediatric Oncologic Surgeons. The Authors summarize the feasibility of MIS, when performed with different purposes (biopsy / resection) and timing (initial / delayed surgery) for the most common solid tumours in children. The oncologic criteria must be always followed with MIS as well as with "open" surgery.

Prevalence of pain in the departments of surgery and oncohematology of a paediatric hospital that has joined the project "Towards pain free hospital".

BACKGROUND: Among hospitalized adults and children pain is undertreated. This study wants to assess the effectiveness of pain therapy in two departments of a large children's hospital. MATERIALS AND METHODS: During a single day work three committees, administering a questionnaire to patients or parents, have evaluated the adherence to international recommendations (JCI and WHO) in the management of analgesic therapy. Patient demographics, prevalence and intensity (moderate and/or severe) of pain (during hospitalization, 24 hours before and at the time of the interview), analgesia (type, route, duration and frequency of administration) and Pain Management Index (=analgesic score-pain score) were recorded. RESULTS: 75 patients participated in the study (age: 2 months up to 24 years, mean 7.8 ± 6). During hospitalization 43 children (57%) had no pain while 32 (43%) have experienced pain. 22 children (29 %) had pain 24 hours before and 12 (16%) at the time of the interview. The average value of the PMI was -0.8±1.3 with a minimum of -3 and a maximum of +2: 60% (19) of the children had a PMI less than 0 (undertreated pain) while 40% (13) had a value=or>0. Out of 32 patients who needed an analgesic therapy 14 (44%) received an around-the-clock dosing, 8 (25%) an intermittent therapy and 10 (31%) no treatment.17 (77 %) were the single drug therapy and 5 (23%) the multimodal ones. CONCLUSIONS: The prevalence of pain in the two departments is high. The main cause is that knowledge is not still well translated into clinical practice.

D-CECaT as preoperative chemotherapy for unresectable neuroblastoma in children over one year of age.

The role of intensive pre- and postoperative chemotherapy in unresectable nonmetastatic neuroblastoma is still controversial. A preoperative regimen that included deferoxamine, cyclophosphamide, etoposide, carboplatin and thiotepa (D-CECaT) was evaluated in 10 children over one year of age at diagnosis, and this was followed by surgery and postoperative chemotherapy. After four courses of D-CECaT, the response rate was 9/10 with 3 complete responses, 6 partial responses and 1 minor response. Severe but transitory myelosuppression was the major toxic effect. Complete remission by combined D-CECaT chemotherapy and surgery was obtained in 9/10 patients, while 1 case achieved complete remission only with postoperative chemotherapy. All children are disease-free with a median follow-up of 30.5 months (range: 1+ to 50+). This intensive treatment was effective in both standard- and high-risk unresectable NB. However, whether a less intensive approach and fewer courses can also give similar results in standard-risk cases warrants further study.

Myofibroblastic tumours: neoplasias with divergent behaviour. Ultrastructural and flow cytometric analysis.

Myofibroblasts are spindle cells having ultrastructural features in common with smooth muscle cells and fibroblasts. In the last few years, tumours have been described in which myofibroblasts represent not only a reactive mechanism but also a true neoplastic component. They constitute new nosologic entities which might be termed "myofibroblastic tumours". Tumours with benign and, rarely, malignant behaviour are reported to belong to this group of lesions. Recently, a third tumour type with borderline biological course, named "inflammatory myofibroblastic tumour" (IMT), has been identified, a condition that has been regarded as a benign and reactive disorder for a long time. Only in recent reports has been demonstrated that, in spite of an apparently benign morphological pattern, some cases of IMT have a malignant course. In this connection, DNA analysis by flow cytometry is a valuable diagnostic tool, because it allows identification of the ploidy status, a procedure that is often useful for predicting the nature and the biological behaviour of the lesion. In this study, 11 cases of myofibroblastic tumours were examined retrospectively by evaluating clinicopathological features and DNA ploidy status by flow cytometry. The diagnosis of myofibroblastic tumour was confirmed by performing histology, immunohistochemistry, and electron microscopy in all patients. In detail, these 11 cases were composed of 1 benign myofibroblastoma, 1 myofibrosarcoma and 9 IMTs. Among these myofibroblastic tumours, all those with local recurrence or distant metastases (one myofibrosarcoma and three IMT) showed an aneuploid cell population demonstrable by flow cytometric analysis, whereas the other cases with benign course (one benign myofibroblastoma and six IMT) exhibited an euploid DNA content. These data suggest the following: a) Besides the rare myofibroblastomas and myofibrosarcomas, IMTs represent a larger group of lesions with potentially different biological and clinical course. b) DNA flow cytometric analysis is a reliable tool that support histopathological examination in characterizing those cases of IMT that, though being malignant, mimic benign lesions. Consequently, it establishes the basis for a different therapeutic approach according to the euploid or aneuploid DNA content.

Neurotensin localization in adenomatoid cystic malformation versus normal lung: preliminary report of six consecutive cases.

Neuropeptides are considered a new class of neurotransmitters, several of which interact with the immune system as well as the macrophagic activity. Among these, neurotensin (NT) enhances the phagocitic response of macrophages and is the only neuropeptide that can enhance the cytolytic effects of activated macrophages. In this way, it may play a role as an inflammatory mediator. In order to investigate the possible relationship between NT and the defence mechanisms of the lung, we started to localize the presence of NT in pulmonary adenomatoid cystic malformation (CCAM). This series consists of 6 children affected by CCAM. In every case, at operation, we obtained specimens of both normal and pathological lung. Tissue sections from the pathological lung showed a significant increase of NT-like immunoreactivity in respect to sections of normal lung. NT influences and activates the macrophages, thus suggesting that it could represent a defence mechanism in children's lung activated in some malformative conditions. Finally, the increasing evidence of NT immunoreactivity in CCAM could explicate an in utero infectious pathogenesis of this malformation.

Features and outcome of neuroblastoma detected before birth.

BACKGROUND/PURPOSE: The growing use of routine ultrasonography during pregnancy is leading to an increasing number of prenatally diagnosed neuroblastomas. Optimal strategy has not yet been defined for these patients, because knowledge on this particular neuroblastoma (NB) population is still limited. However, definite guidelines are needed to avoid inadequate treatment. The authors analyzed the cases of antenatally detected NB (ADNB) reported in the Italian Neuroblastoma Registry during the past 6 years to elucidate the features of this subset of NB. METHODS: The Italian Neuroblastoma Registry was reviewed for the period January 1993 to December 1998 to collect clinical, radiographic, surgical, and histopathological data on ADNB cases. NB stage was evaluated according to INSS criteria. All patients had undergone imaging (computed tomography or magnetic resonance imaging) of the primary tumor and bone marrow biopsy before surgical resection. RESULTS: Seventeen patients were identified. Primary tumour site was adrenal glands in 16 cases and retroperitoneal ganglia in 1. Stage distribution was stage I, 13 cases; stage II-A, 1 case; stage II-B, 1 case; stage IV-S, 2 cases. All cases underwent primary tumour resection. Mean age at surgery was 4 weeks. Resection of primary tumor was radical in 16 cases, partial in 1. All tumors were characterised by favourable histology according to Shimada classification. N-myc gene amplification was studied in 14 patients. N-myc amplification was detected only in a newborn with stage II-A NB, who died of massive bleeding 2 days after tumor resection. DNA index and 1p deletion were studied in 11 and 8 patients, respectively. Both diploidy and deletion of 1p were observed in a newborn who subsequently died of disease progression despite surgery, chemotherapy, and radiation therapy. Fourteen of 17 patients currently are alive and free of disease, and one with IV-S NB and short follow-up is alive with disease. CONCLUSIONS: Our data give evidence that in most cases infants with ADNB represent a subset of patients with excellent outcome. Aggressive treatment may not always be necessary. Infants with ADNB with unfavorable features should undergo early surgical excision, whereas patients with favourable features could be observed awaiting spontaneous regression of the mass, reserving delayed surgery for tumors that increase in size or do not regress.

[Echinococcosis/hydatidosis in children: combined medical and surgical treatment]. / Echinococcosi/idatidosi in età pediatrica: trattamento combinato medico-chirurgico.

The outcome of 5 children with visceral hydatid cysts treated with Albendazole and surgical therapy is reviewed. The diagnoses were confirmed by immunological tests, X-ray, ultrasound scanner (US) and computer tomography. The therapeutic approach was correlated to the type of infection pictures. Immunological tests, X-ray and US were performed with the aim to evaluate the response to the therapeutic protocol. Combination of pharmacological and surgical treatment resulted in a complete resolution for all patients without any recurrence and further dissemination of infection.

A single-institution Wilms' tumor and localized neuroblastoma series.

Since January 1980, 120 children affected by Wilms' tumor have been treated at Bambino Gesù, mostly with multimodality treatment according to Société Internationale d'Oncologie Pediatrique (SIOP) protocols, including chemotherapy, surgery and radiotherapy in selected cases. This treatment approach emphasizes the role of preoperative (neoadjuvant) chemotherapy as opposed to the approach favored by the National Wilms' Tumor Study, which is focused on optimizing postoperative chemotherapy after primary surgery. Thus, using SIOP guidelines, staging occurs at the time of surgery, after chemotherapy administration. These differences will constitute the baseline for a comparison between the two experiences. Bilaterality, nephroblastomatosis, partial nephrectomy in unilateral Wilms' tumor and thrombosis of the vena cava are the main topics discussed. For the present study, the analysis was restricted to 98 consecutive cases diagnosed until December 1999, for whom at least 24 mo of follow-up is available. The more recent experience of treating resectable neuroblastoma in cooperative studies dates back to 1979, when the first Italian Cooperative Group Neuroblastoma protocol was introduced. This experience was continued within the frame of the first Localized Neuroblastoma European Study Group protocol (LNESG 94), and will be compared to North American Cooperative Group approaches and outcomes. Preoperative evaluation of surgical risk factors, intraoperative complications and their management, and long-term outcome will be discussed.

Ifosfamide/carboplatin/etoposide (ICE) as front-line, topotecan/cyclophosphamide as second-line and oral temozolomide as third-line treatment for advanced neuroblastoma over one year of age.

Children affected by advanced neuroblastoma have a discouraging prognosis, but intensive induction chemotherapy may increase the complete response rate. The combination of ifosfamide, carboplatin and etoposide (ICE) was used for the first time as front-line regimen in patients with stage 4 neuroblastoma over the age of 1 y. Similarly, second-line treatment for children with relapsed neuroblastoma, particularly after high-dose chemotherapy, has been unsatisfactory. The combination of topotecan and cyclophosphamide was studied in resistant or relapsed solid tumors. Furthermore, there is a need for effective palliative treatment in patients failing therapy. Temozolomide, a new dacarbazine analog with optimal oral bioavailability, is being used in an ongoing phase II study as an alternative to oral etoposide. Seventeen patients with stage 4 neuroblastoma have entered the ICE study; 15/16 (94%) major responses after induction were observed and 6/16 (37%) evaluable patients are disease free after a median of 51 mo. Twenty-one patients with relapsed/refractory disease (of whom 13 neuroblastomas) entered the topotecan/cyclophosphamide study: 7/21 (33%) patients responded. Forty-one patients entered the temozolomide study (of whom 16 had neuroblastomas): stable disease and symptom relief were obtained in 15/30 (50%) evaluable patients. Intensive induction with ICE resulted in a faster response with high response rate; a larger study with longer follow-up is needed to confirm a survival advantage. Second-line treatment was effective in obtaining remissions, some of them long lasting. Third-line treatment did not elicit measurable responses in neuroblastoma, but achieved prolonged freedom from disease progression and excellent palliation in several patients.

[Experience in the prophylactic use of ceftriaxone in pediatric surgery]. / Esperienze sull'uso profilattico del ceftriaxone in chirurgia pediatrica.

Authors report on their experience about ceftriaxone in surgical prophylaxis in childhood. 30 patients have been treated, suffering from surgical diseases, either thoracic or abdominal ones, including malignancies. Ceftriaxone was administered once a day; patients received ceftriaxone only once preoperatively: Results have been very satisfactory, the only two complications having been found in two severely immunocompromised patients.

[Surgery of thyroglossal duct in childhood]. / La chirurgia del dotto tireoglosso in età pediatrica.

A retrospective review of 177 neck masses in childhood treated between January 1975 and December 1990 at the "Bambino Gesù" Pediatric Hospital of Rome is presented, with particular emphasis on recurrences and their causes. 105, object of our study, were thyroglossal duct cysts (TDC) (58.7%); in the remaining 72 cases there were dermoid cysts (23.1%), granulomas (7.9%), lateral neck masses (1.69%) and other histological patterns. The aim was to identify the variables that could change postoperative hospitalization or cause the recurrence. The TDC's group was separated in two: 92 primary patients, while 13 received a preliminary operation in other institutions. In the first group we applied 41 Sistrunk, 43 Schlange, 8 cystectomies; 5 recurrences occurred (5.43%), 3 of which in patients operated on with modified Sistrunk's technique (Schlange) (60%). In the second group (13 patients) a standard Sistrunk procedure was always performed. We had only one recurrence (7.69%) due to a remnant of multiple proximal thyroglossal duct. In 11 cases (10.47%) there were postoperative complications due to an existing inflammatory condition of the TDC (8 patients -72.72%). In only one case there was a recurrence after 27 months. Histological study of the specimens showed that thyroglossal ducts were frequently multiple and widely spaced and may also be present in the distal portion of the duct; in our series in 16.19% we found the distal portion of the duct during the operation. Our overall recurrence frequency is 5.7%. Every lesion referred to a TDC must be treated with a Sistrunk procedure for the better results achieved with this surgical approach but, in our experience, we prefer to complete the Sistrunk's technique with the research and exeresis of the distal portion of the duct by a "muscular sparing procedure" that preserves little patients from pharyngodynia. At the follow-up, we have not recurrence in the 17 cases operated on by this procedure.

[Peripheral neuroectodermal tumors of the chest wall. Description of a case]. / Tumori neuroectodermici periferici della parete toracica. Descrizione di un caso.

The authors discuss a case of malignant small round cell tumor of the thoracopulmonary region (Askin tumor) in which the initial pathological diagnosis was "sarcoma". Only a review of the histological specimens and the clinical features and evolution revealed the correct diagnosis of "Askin tumor". A 15 year old girl with fever, dyspnoea, cough underwent thoracentesis, which revealed hemothorax. At surgery, a large mass not involving the lung, with pleural thickening, was found in the left hemithorax and excised, without rib resection. No metastasis was observed at that time. Histological findings revealed features of malignant small round cell tumors, with occasional pseudo-rosettes. Chemotherapy was performed. 16 months after clinical presentation the girl died with abdomino-thoracic metastatic disease.

[Persistent multiple urachal complex. Echographic-surgical correlations]. / Complesso uracale multiplo persistente. Correlazione ecografico-chirurgica.

Urachus is a tubular structure lined between foetal bladder and the umbilicus and is susceptible to complete or partial involution after birth. Persistence of the urachus results in a wide spectrum of anomalies: patent urachus, vesicourachal diverticulum, urachal sinus and cysts are more frequently seen than rare multiple urachal remnants. This kind of pathology focuses the problem of differential diagnosis (tumours, omental and ovarian cysts, vesical diverticulum or duplication) and may be complicated by a superinfection. The Authors discuss a bizarre multiple urachal remnant, presenting with urinary tract symptoms, which may be clinically confused with acute appendicitis or Meckel's diverticulitis. Contribution of sonography for a complete diagnosis is stressed, such as the precise correlation with surgical findings.

Mesosigmoidoplasty in the treatment of sigmoid volvulus in children.

Sigmoid volvulus is a rare disease of childhood, which requires surgery. The case of a 12-year-old boy is reported. The main aetiopathogenetic causes and the proper surgical approach are also described with particular reference to the so-called mesosigmoidoplasty, which consists of shortening the mesosigmoid by incision along its axis and transverse suture.