Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment. We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374. We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28-61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3-4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths. Although the combination of sorafenib and everolimus showed activity as a further-line treatment for patients with advanced or unresectable osteosarcoma, it did not attain the prespecified target of 6 month PFS of 50% or greater. Italian Sarcoma Group.

It is generally believed that in gluten-sensitive enteropathy or celiac disease (CD), mucosal lesions may have a patchy distribution. We wanted to verify this concept and establish whether one or more biopsy samples are needed in order to make a correct diagnosis of CD. One hundred and twelve consecutive children with positive antiendomysium (EMA) or antitissue transglutaminase (tTGA) antibodies, referred to us for suspected CD, were enrolled in a prospective fashion. During upper GI endoscopy four to five biopsies were taken from Treitz and/or distal duodenum (D3), intermediate duodenum (D2), proximal duodenum (D1), and duodenal bulb (B). Histologic lesions were classified according to Marsh criteria modified by Oberhuber. A total of 110 patients, all HLA-DQ2 or DQ8 positive, had a final diagnosis of CD (59 classic, 28 atypical, and 23 silent): 102/110 (92.7%) had type 3 lesion—(a) mild, (b) moderate, or (c) severe—in at least one site and 94/110 (85.4%) had villous atrophy (VA) of some degree in all sites. VA of identical degree was present in all biopsy sites in 55/110 (50%) patients. Total VA (type 3c) was present in at least one site in 85/110 (75%), in all sites in 50/110 (45.4%), and significantly increased in aborad direction ((χ² > 26.22 with (= 0.01 and d.f. (degrees of freedom) = 12). Eight out of 110 (7.2%) CD patients had exclusively type 1 or 2 lesions, no patient had lesion variability >1 degree and none had normal biopsies. There was no correlation between type or distribution of histologic lesions and clinical presentation of CD. Mucosal atrophy is present in 85% of patients with CD and total VA is significantly more frequent in distal duodenum or proximal jejunum. Fifty percent of patients have identical VA throughout the duodenum and no duodenal areas are histologically normal. In genetically susceptible children with positive serology, a diagnosis of CD can reliably be made even if biopsies are not taken from the distal duodenum or jejunum.

Introduction: The EUROpean Bone Over 40 Sarcoma Study (EURO-B.O.S.S.) was the first prospective international study for patients 41-65 years old with high-grade bone sarcoma treated with an intensive chemotherapy regimen derived from protocols for younger patients with high-grade skeletal osteosarcoma. Methods: Chemotherapy based on doxorubicin, cisplatin, ifosfamide, and methotrexate was suggested, but patients treated with other regimens at the investigators’ choice were also eligible for the study. Results: The present report focuses on the subgroup of 218 patients with primary high-grade osteosarcoma. With a median follow-up of 47 months, the 5-year probability of overall survival (OS) was 66% in patients with localized disease and 22% in case of synchronous metastases. The 5-year OS in patients with localized disease was 29% in pelvic tumors, and 70% and 73% for extremity or craniofacial locations, respectively. In primary chemotherapy, tumor necrosis ≥90% was reported in 21% of the patients. There were no toxic deaths; however, hematological toxicity was considerable with 32% of patients experiencing 1 or more episodes of neutropenic fever. The incidence of nephrotoxicity and neurotoxicity (mainly peripheral) was 28% and 24%, respectively. After methotrexate, 23% of patients experienced delayed excretion, in 4 cases with nephrotoxicity. Conclusions: In patients over 40 years of age with primary high-grade osteosarcoma, an aggressive approach with chemotherapy and surgery can offer the probability of survival similar to that achieved in younger patients. Chemotherapy-related toxicity is significant and generally higher than that reported in younger cohorts of osteosarcoma patients treated with more intensive regimens.