Integrating system biology and intratumor gene therapy by trans-complementing the appropriate co-stimulatory molecule as payload in oncolytic herpes virus.

Systems biology has been applied at the multi-scale level within the cancer field, improving cancer prevention, diagnosis and enabling precision medicine approaches. While systems biology can expand the knowledge and skills for oncological treatment, it also represents a challenging expedition due to cancer complexity, heterogeneity and diversity not only between different cancer indications, but also in its evolution process through space and time. Here, by characterizing the transcriptional perturbations of the tumor microenvironment induced by oncolytic, we aimed to rationally design a novel armed oncolytic herpes virus. We found that intratumor oncovirotherapy with HSV-1 induces T-cell activation signatures and transcriptionally activates several costimulatory molecules. We identified differentially expressed costimulatory receptors and binding partners, where inducible co-stimulators (ICOS) resulted in the potentially most beneficial targeted therapy. Through an ex-vivo transcriptomic analysis, we explored the potential of arming an oncolytic virus as a combination therapy strategy; in particular, we engineered a targeted herpes virus encoding ICOSL (THV_ICOSL), which resulted in a significant improvement in tumor size control compared to unarmed parental virus. Also, combination with a PD-1 inhibitor enhanced antitumor efficacy as predictable by upregulation of PD-1 and ligands pair (PD-L1/PD-L2) upon oncolytic virus injection. Generation of the human version of this virus encoding hICOSL orthologue effectively and specifically activated human T cells by triggering the ICOS pathway. Our data support the data-driven generation of armed oncolytic viruses as combination immunotherapeutic with checkpoint inhibitors.

Vitamin D status of inmates: the experience of penitentiaries prisons in the province of Salerno in Southern Italy.

Introduction: Prisoners are at risk of developing vitamin D deficiency due to their lacking exposure to sunlight. So far, there are no published studies evaluating blood levels of vitamin D in relation to the health status of inmates and the quality of the Italian prison system. Aim: To investigate vitamin D status and its determinants in a cohort of prisoners. Subject and Methods: One hundred and seventy-two (172) pri-son inmates (males, n=159, age 47± 11.3 years; females, n=13, age 43.91±12.18 years) of three penitentiaries in the province of Salerno. Vitamin D deficiency, insufficiency and sufficiency were respectively defined as a 25(OH)D level <20 ng/mL; from 20 to 30 ng/mL, >30 ng/mL. Results: In our group, Vitamin D deficiency occurs in 77.32% of the prisoners with 32.55% of the cases having severe insufficiency. Prisoners with higher BMI show lower circulating vitamin D levels (p<0.001). No significant relationship was found with the duration of detention (Pearson R: 0.01). Conclusion: In this cohort of inmates the vitamin D status is determined by BMI, but not by the duration of the detention.

Merkel cell carcinoma: experience of 14 cases and literature review.

Merkel cell carcinoma is an aggressive skin cancer, with a significant incidence of locoregional lymphnode involvement, which requires timely diagnosis, adequate staging and aggressive therapy based essentially on surgical procedures. The aim of this study is to report our experience and to compare our results with literature findings, in order to discuss the role of the procedures adopted and their influence on prognosis. From July 1995 to April 2005, 14 patients were treated and followed-up for MCC in the National Cancer Institute of Naples. Tumor location was: buttocks (43%), extremities (36%) head (7%), unknown (14%). There were 7 Stage I, 5 Stage II and 2 Stage III patients. Surgical treatment consisted in wide excision (WE) in Stage I cases, WE and regional lymphadenectomy followed by radio- or chemo-therapy in Stage II and combined surgical and pre- and post-operative medical treatments in Stage III. Overall disease specific survival rate was 64% (median follow up 44 months). Recurrence occurred in 86% of Stage I and 20% of Stage II patients and involved, in 83.3% of Stage I patients, the lymph nodal draining basin. The treatment of recurrence implied surgery and radio or radiochemotherapy. Overall survival rate of recurrent patients was 57% (median follow-up 37.2 months). Due to the particular lymphotrophism of MCC, major care should be set on investigation and treatment of tumor lymph nodal draining basin. As long as the disease remains surgically manageable the prognosis for patients with MCC is favourable. The role of radio and chemotherapy is not yet assessed.

Expression of CD40 has no predictive value in soft tissue sarcomas.

BACKGROUND: CD40, a member of the tumor necrosis factor receptor superfamily, is capable of mediating the induction of apoptosis in tumors including sarcomas. The expression of proapoptotic receptor contribute to the induction of apoptosis by chemotherapeutic drugs. The present study was undertaken to determine if there is a correlation between the expression of CD40 in spindle-cell sarcomas and the response to epirubicin and ifosfamide chemotherapy. PATIENTS AND METHODS: Immunohistochemical analysis of CD40 expression was performed on 59 paraffin-embedded archival tissues. Evaluation of objective tumor response was carried out according to the WHO criteria. Correlations with response to chemotherapy and baseline patients' characteristics were investigated using Chi-square tests. RESULTS: Positive CD40 staining was observed in 42 tumors; it was expressed in < 10% of cells in 14 (24%), in 10 to 50% in 16 (27%) and in more than 50% of cells in 12 (20%) tumors. No significant association was found between CD40 expression, response to chemotherapy and other clinical and pathological characteristics. CONCLUSION: CD40 expression in spindle-cell soft tissue sarcomas is not associated with response to ifosfamide plus epirubicin chemotherapy.

Neoadjuvant chemotherapy for intermediate/high-grade soft tissue sarcomas: five-year results with epirubicin and ifosfamide.

BACKGROUND: Neoadjuvant chemotherapy for intermediate/high-grade soft tissue sarcomas (STS) may provide some advantages for facilitating the surgical resection of the tumor and for disease control. However its role as induction therapy before surgery should still be proved. PATIENTS AND METHODS: Twenty-one patients with intermediate/high-grade STS and tumor size > or = 5 cm were consecutively treated from 1997 to 2001 with neoadjuvant chemotherapy based on epirubicin 60 mg/m2/day on days 1 and 2 and ifosfamide 1.8 gr/m2/day on days 1 through 5 every three weeks. Evaluation of objective tumor response and toxicity were carried out according to WHO criteria. RESULTS: Nine partial responses were documented; stable disease in 11 patients, progressive disease in one patient. Apart from nine cases of grade 4 neutropenia, the treatment was generally well-tolerated. Twelve patients underwent conservative and limb salvage surgery. CONCLUSION: This therapeutic approach seems to be effective in facilitating surgery. Neutropenia was the most significant toxicity but it was preventable or medically treatable with G-CSF support.

Primary plasmacytoma of the breast.

We describe a solitary extramedullary plasmacytoma of the breast in a 37-year-old woman. No other involvement was detected in the bone marrow or in any other site during a 15-month follow-up period. Extramedullary plasmacytomas of the breast are extremely rare, especially those that are not associated with multiple myeloma. We review the histologic features of the previously reported cases with an emphasis on differential diagnosis and the difficulties encountered in arriving at the correct diagnosis in frozen sections.

Leiomyosarcoma of the Oropharynx and Neurogenic Tumors in a Young Patient With Turner's Syndrome.

PATIENT: A case of Turner's syndrome developing a leiomyosarcoma of the oropharynx and metachronous neurogenic tumors (mediastinal 'ganglioneuroblastoma intermixed', subcutaneous neurilemoma) is described. DISCUSSION: To our knowledge, this case is the second reported leiomyosarcoma in a patient with Turner's syndrome. Also the site of involvement (palate and oropharynx) is particularly unusual for the already rare leiomyosarcomas in the young age.

Warthin-like tumour of the thyroid gland: RET/PTC expression indicates it is a variant of papillary carcinoma.

AIMS: Three cases with features of so-called 'Warthin-like tumour' of the thyroid (WaLTT) are described, in order to evaluate its relationship with papillary carcinoma (PC). METHODS AND RESULTS: We performed an histological and immunohistochemical study with emphasis on RET/PTC expression. The most striking features are represented by marked lymphocytic infiltration in the stalks of papillae and by oxyphilic metaplasia of epithelium, resembling Warthin tumour of the salivary gland. In all cases, we found nuclear features reminiscent of PC. The neoplastic cells were strongly positive for Leu M1 and epithelial membrane antigen (EMA), less for thyroglobulin and negative for calcitonin. The lymphocytic infiltrate was composed of a mixed population of B and T-cells with sparse S100-positive Langerhans cells. An interesting finding was the strong positivity with the antibody against RET/PTC. CONCLUSION: All clinicopathological data along with the presence of the extensive lymphocytic infiltrate could imply a more favourable prognosis. The expression of RET/PTC fusion gene adds support to the hypothesis that this tumour is a variant of PC, probably related to the oncocytic variant of PC.

Granular cell tumors of the colon: report of a case and review of the literature.

Granular cell tumors are uncommon, usually benign tumors that can be located anywhere in the body. They commonly occur in the oral cavity and in subcutaneous tissue. In the gastrointestinal tract, granular cell tumors are uncommon and are quite rare in the colon. To date, 55 patients diagnosed with granular cell tumors of the colon have been reported in the literature, only 15 had multiple tumors. We describe the case of a 38-year-old man with a family history of colon cancer who was diagnosed with multiple colonic granular cell tumors after a screening colonoscopy. This seems to be the first report of this type. However, in our patient, the diagnosis of colonic granular cell tumors was incidental and there is no data that correlates adenomas or colorectal cancer with granular cell tumors of the colon. Finally, since granular cell tumors are usually benign, we suggest a conservative approach to patients with multiple granular cell tumors of the colon by means of endoscopic resection and a strict endoscopic follow-up.

[Laryngeal mask as alternative to facial mask in the newborn]. / La maschera laringea in alternativa alla maschera facciale nel neonato.

OBJECTIVE: The present study demonstrates that the use of laryngeal mask airway (LMA) is an alternative to face-mask (FM) during induction of general anesthesia with halothane. In all patient the induction of general anesthesia is carried out by halotane and N2O/O2 50%, using only the LMA, preceding topical anesthesia of pharynx. EXPERIMENTAL DESIGN: prospective study. SETTING: this study was carried out at the surgical-division of the Pediatric Clinic, of University "La Sapienza", Rome. PATIENTS: a total of 80 newborns, average age 14.8 +/- 2.4 days and average body weight 2280 +/- 110 g were examined. INTERVENTIONS: newborns were submitted to surgery for congenital malformations, diagnostic research and positioning of a central venous catheter (CVC). MEASUREMENTS: Heart rate, non-invasive arterial pressure through cardiomonitor Hewlett Packard 78352A, oxygen saturation through Nellcor N3000, time of induction of general anesthesia and respiratory rate were assessed. RESULTS: Blood pressure and heart rate were increased during the positioning of LMA; oxygen saturation remained > or = 94% and respiratory rate was constant during the whole observation. Muscular relaxing, as an index of anesthesia, was observed after 33 +/- 1.5 sec after positioning of LMA. CONCLUSIONS: In the light of the results obtained, the use of the LMA for airway ventilation during the induction period of pediatric anesthesia is suggested.

Multicentric giant cell tumor with viral-like inclusions associated with Paget's disease of bone: a case treated by steroid therapy.

We report a case of giant cell tumor of bone (GCTB) associated with Paget's disease unsuccefully treated with radiotherapy for some years but dramatically reduced in size with high dose of dexamethasone within few days. An ultrastructural study showed intranuclear virus-like inclusions in the multinucleated giant cells. The patient was then switched to prednisone plus diclofenac and he is still in almost complete remission after two years. The patient was from Avellino area, a small town in Southern Italy.

[Use of new elastomeric pumps and PCA in postoperative pain control in thoraco-abdominal surgery]. / Impiego di nuove pompe elastometriche e della PCA nel controllo del dolore post-operatorio in chirurgia toraco-addominale.

36 patients submitted to interventions for thoraco-abdominal surgery has been submitted to antalgic post-operatory therapy with elastomeric pump at a continuous intravenous infusion and patient controlled analgesia (PCA). The patients have been randomized in three groups. The patients of the 1 degree group received 30 minutes before of the end of the surgical intervention 30 mg of Ketorolac. At the end of the anesthesia came started an infusion of 150 mg of Ketorolac (5 vials) in 60 ml of isotonic chlorinated solution at the rate of 0.5 ml/h. The pump had besides the capability of disperse a maximum of 4 bolus/ h, everyone of 0.5 ml, on demand of the patient. The 2 degrees group received a solution containing 60 ml of Morphine in 60 ml of isotonic chlorinated solution with the same formality of administration. The 3 degrees group (placebo) received 60 ml of isotonic chlorinated solution in pumps from infusion and Ketorolac intramuscular on demand. To the times T0 (awakening), T1 (3 h), T2 (6h), T3 (12 h), T4 (24 h), T5 (30 h, was collected algometrical consequences according to VAS (Visual Analogous Scale of Sc modification of the PA increase, FC, FR, SatO2.. The obtained results have highlighted like in the 1 degree group, to the 1 degree algometric consequence (T0), there is a good sedative effect on the pain (intensity of the middle low pain 3.70 +/- 1.64); this antalgic effect has also continued in the other consequences effected in the post-operatory. In the 2 degree group to the awakening (T0), the pain was middle-tall (5.50 +/- 2.32) and an expressive reduction appeared at the time T2 (3.60 +/- 1.35 P < 0.005). In the 3 degrees group have not recorded a diminution of the pain if not after 24 hours from the end of the intervention deposit the intramuscular antalgic therapy. In conclusion, the system infusion + PCA represents an indubitable advantage in comparison with the traditional antalgic therapy as for concern the entity of the reduction of the pain as because it permits the use of a smaller quality of drugs.

[Diagnosis of food allergy caused by fruit and vegetables in children with atopic dermatitis]. / Diagnosi di allergia alimentare a frutta e verdura in bambini affetti da dermatite atopica.

Atopic dermatitis (A.D.) is a frequent, complex and multifactorial disease: Food Allergy (F.A.), probably underestimated, especially for fruits and vegetables, seems to play an important pathogenetic role in children. The purpose of this study is to estimate, on a sample of children with A.D., the prevalence of F.A. (for fruits and vegetables), and the reliability of diagnosis of Prick+Prick test compared with the usual Prick test, RAST and challenge. Twentysix patients (17 M and 9 F), ranging in age from 5 months to 8 years, were enrolled in the study. All fulfilled the criteria of Hanifin and Rajka for the diagnosis of A.D. Food RAST, prick tests with inhalant and food extracts and Prick+Prick tests with fresh fruits and vegetables were carried out. In the case of positive result to fruits and vegetables with skin tests and/or RAST, open challenge for every type of food considered responsible was carried out, after healing or improvement of dermatitis. Three children (11.53%) suffered from F.A. for fruits and vegetables: allergy to celery of one patient was discovered only by usual Prick test; allergy to tomato and kiwi in another patient was spotted by Prick+Prick only; while in another case by both tests. In this last patient Prick+Prick test revealed a real allergy for 5 aliments (carrot, tomato, celery, cucumber, fennel) of which only 2 (carrot and celery) also caused a reaction with the Prick test. The combined use of both tests made it possible to increase the diagnosis of F.A. both for the number of patients and for a complete identification of implicated foods.