Combination of letrozole, metronomic cyclophosphamide and sorafenib is well-tolerated and shows activity in patients with primary breast cancer.

PURPOSE: To assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC). METHODS: Thirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers. RESULTS: Adequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by (18)FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively). CONCLUSIONS: The LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is clinically and biologically active.

Prospective neoadjuvant analysis of PET imaging and mechanisms of resistance to Trastuzumab shows role of HIF1 and autophagy.

BACKGROUND: Although Trastuzumab has improved survival of HER2+ breast cancer patients, resistance to the agent pre-exists or develops through the course of therapy. Here we show that a specific metabolism and autophagy-related cancer cell phenotype relates to resistance of HER2+ breast cancer to Trastuzumab and chemotherapy. METHODS: Twenty-eight patients with locally advanced primary breast cancer were prospectively scheduled to received one cycle of Trastuzumab followed by a new biopsy on day 21, followed by taxol/Trastuzumab chemotherapy for four cycles before surgery. FDG PET/CT scan was used to monitor tumour response. Tissue samples were immunohistochemically analysed for metabolism and autophagy markers. RESULTS: In pre-Trastuzumab biopsies, the LC3A+/HER2+ cell population was correlated with HIF1α expression (P=0.01), while GLUT1 and LC3B expression were correlated with Ki67 proliferation index (P=0.01 and P=0.01, respectively). FDG PET tumour dimensions before therapy were correlated with LC3B expression (P=0.005). Administration of Trastuzumab significantly reduced clinical and PET-detected tumour dimensions (P<0.01). An inverse association of tumour response with the percentage of cells expressing HIF1α at baseline was documented (P=0.01). Administration of Trastuzumab resulted in a decrease of the proliferation index (P=0.004), GLUT1 (P=0.04) and HER2 (P=0.01) expression. In contrast, the percentage of LC3A+/HER2+ cells was increased (P=0.01). High baseline HIF1α expression was the only parameter associated with poorer pathological response to preoperative chemotherapy (P=0.001). CONCLUSIONS: As the HER2+/LC3A+ phenotype, which often overexpresses HIF1α, is a major subpopulation increasing after therapy with Trastuzumab, LC3A- and HIF1α-targeting therapies should be investigated for the augmentation of anti-HER2 therapy efficacy.

[Idiopathic retroperitoneal fibrosis]. / La fibrosi retroperitoneale idiopatica.

Retroperitoneal fibrosis is an uncommon disease, characterized by the replacement of normal retroperitoneal tissue with fibrosis and/or chronic inflammation. In two thirds of the cases retroperitoneal fibrosis is idiopathic (IRF), whereas in the remaining ones it is secondary/associated to cancer, infections, drugs, autoimmune disease and vasculitis. IRF appears as a dense, fibrous plaque that usually arises between the level of the lower aorta and the common iliac arteries. As the plaque progresses, it engulfs the adjacent structures (e. g., ureters). In its early stages IRF is characterized by a rich infiltrate of lymphocytes, plasma cells and macrophages interspersed within fibroblasts and collagen bundles. In its advanced stages it becomes relatively avascular and acellular with abundant collagen bundles and scattered calcifications. The pathogenesis is unknown: some Authors suggest that IRF is a consequence of a local autoimmune reaction against atherosclerotic plaque antigens whereas others propose that it is the manifestation of a systemic autoimmune disease. The presenting signs and symptoms are non-specific; systemic manifestations (fever, anorexia, weight loss), often associated with local symptoms, are usually found to be related to the entrapment of retroperitoneal structures. The most common local symptom is lumbar and/or abdominal pain. The treatment can be surgical and/or medical: the former is required when obstructive complications are present; the latter, associated or not with surgery, can significantly improve the outcome of IRF patients and usually modifies the natural history of the disease. Steroids and tamoxifen are the most used drugs, whereas other agents such as azathioprine, methotrexate and cyclosporine are usually given to non-responder patients.

Structural changes induced by antineoplastic therapies: keys to evaluate tumor response to treatment.

The criteria to define therapeutic response in oncology are those proposed by Miller, characterized by four response categories (complete response, partial response, no change, progression of disease), and based upon both measurable and non-measurable (and otherwise assessable) morphological parameters in comparison with baseline and subsequently modified following the Response Evaluation Criteria In Solid Tumors. In addition to these classical morphological criteria, we review the predictive value of structural changes in the evaluation of response to antineoplastic therapies. The goal of the present review is to evaluate in detail structural variations (calcification, fibrosis, differentiation, necrosis, cavitation, vascularization, edema, and pseudocapsule formation) induced by therapy, and to ascertain their significance in terms of biological evolution of the neoplastic process.

ANCA-positive periaortic vasculitis: does it fall within the spectrum of vasculitis?

Retroperitoneal fibrosis (RPF) is a disease of unknown aetiology that has sometimes been reported in association with connective tissue disorders and systemic vasculitis. We report here two cases of antineutrophil cytoplasmic antibody (ANCA)-positive RPF showing clinical evidence of rapidly progressive glomerulonephritis. Although treatment with prednisone and cyclophosphamide led to a remission of RPF in both cases, renal function was restored in only one patient and the other progressed to chronic renal failure. The paper reviews the literature concerning ANCA-positive RPF and discusses the relationship between ANCA-positive vasculitis and RPF.

Long-term immunotherapy with low-dose interleukin-2 and interferon-alpha in the treatment of patients with advanced renal cell carcinoma.

BACKGROUND: The objective of this study was to evaluate response, toxicity, and immunologic effects of an original immunotherapy schedule based on repeated cycles of low doses of recombinant interleukin-2 (rIL-2) and recombinant interferon-alpha (rIFNalpha) in patients with metastatic renal cell carcinoma (mRCC). METHODS: Fifty patients who underwent nephrectomy received therapeutic cycles consisting of subcutaneous rIL-2 for 5 days per week and intramuscular rIFNalpha twice weekly for 4 consecutive weeks. The cycle was regularly repeated indefinitely at 4-month intervals in all patients, irrespective of their response. rIL-2 (1 x 10(6) IU/m(2)) was administered every 12 hours on Days 1 and 2 and once per day on Days 3-5 of each week; rIFNalpha (1.8 x 10(6) IU/m(2)) was given on Days 3 and 5. Toxicity was graded according to the World Health Organization (WHO) criteria. Forty percent of the patients had only one metastatic disease site at the time of treatment. The Kaplan-Meier method was used to estimate survival, and an analysis of variance was used to evaluate the effects on leukocytes and lymphocyte subsets over time. RESULTS: A total of 241 cycles were administered. One patient achieved a complete response, and five patients achieved a partial response. Five patients had stable disease, and 30 patients had progressive disease. Nine patients were not evaluable for response. The overall response rate was 12% (95% confidence interval, 3-21%) on the basis of an intent-to-treat analysis. The 36-month survival probability for all 50 patients was 47%. Treatment-related toxicity was limited to WHO Grades 1 and 2. Both lymphocyte and eosinophil levels significantly increased after all cycles (by 42% and 353%, respectively). The treatment also induced significant increases in the CD25 positive (24%), CD56 positive (28%), and CD3 negative/CD56 positive (54%) lymphocyte subsets. CONCLUSIONS: Long-term, repeated treatment with low doses of rIL-2 and rIFNalpha is feasible in patients with mRCC. The schedule induces clinical response rates and survival probabilities are similar to those obtained using higher doses.

Focal Castleman disease of the lung: MRI findings.

Castleman disease is an uncommon benign disorder mainly affecting mediastinal lymph nodes and rarely visceral organs. The most typical structural finding is hypervascularity which can be well demonstrated both by CT and MRI. We report MR findings of an unusual case of solitary parenchymal lung involvement.

Enlarging tongue masses in neurofibromatosis type 1: MR findings of two cases.

Plexiform neurofibromas usually occur in the neck, pelvis, and extremities. Jaws and oral cavity plexiform neurofibromas have also been described. Magnetic resonance (MR) patterns for neurofibromas are typical. They include low-to-intermediate signal intensity on T1-weighted images, enhancement of the solid component of the tumor after contrast medium administration, heterogeneity on T2-weighted images, and in some cases, multiple target signs due to a collagen central area. We report MR findings of two neurofibromatosis type 1 (NF1) patients with enlarging tongue plexiform neurofibromas.

Duodenal hemangiopericytoma: CT and MRI findings.

Hemangiopericytoma (HPC) is a rare mesenchymal tumor generally occurring in adults and originating from the pericytes. The tumor more commonly affects the soft tissues of the extremities, the pelvis, and the retroperitoneum. We describe the computed tomographic and magnetic resonance appearance of a patient affected by HPC of the duodenum.

[Optic pathway gliomas in patients with neurofibromatosis type 1: clinical-neuroradiological integrated approach]. / I gliomi delle vie ottiche nei pazienti affetti da neurofibromatosi di tipo 1: approccio integrato clinico-neuroradiologico.

PURPOSE: To evaluate a patient population affected by Neurofibromatosis type 1 (NF1) with special reference to optic pathway gliomas. MATERIAL AND METHODS: A total of 419 NF1 patients (222 men, 197 women) were retrospectively evaluated to show incidence, biological behaviour, neuroradiological and clinical presentation of optic pathway gliomas. Central Nervous System MR and ophthalmologic evaluations were reviewed. RESULTS: Thirty-two patients out of 419 (7.6%) showed the presence of optic pathway gliomas. Of these, 28 (87.2%) patients showed tumoral involvement of the optic chiasma. The right intracranial optic nerve was involved in 15 patients (46.8%), the left intracranial optic nerve in 18 (56.2%), the right extracranial optic nerve in 11 (34.3%), the left extracranial optic nerve in 10 (31.2%) and the right and left optic tracts in 6 (18.7%) patients. Geniculate body and optic radiation were not involved by tumour diffusion. Visual acuity testing was positive in 26/32 (81.2%), the fundus oculi in 11/32 (34.3%) patients and the visual field evaluation in 12/32 (37.5%) patients. CONCLUSIONS: In this study we showed an high correlation between optic pathway tumours and ophthalmologic abnormalities confirming the usefulness of an integrated clinical-neuroradiological approach in patients affected by NF1. We also described the biological behaviour of these tumours in our NF1 patient population.

An unusual MR presentation of the neurohypophyseal "bright spot" in pituitary dwarfism.

Abnormalities of the hypothalamo-hypophyseal axis are frequently associated with pituitary deficiency. We describe a previously unknown morphological presentation of the ectopic posterior neurohypophyseal "bright spot."

Hemangiosarcoma of the adrenal glands: CT findings in two cases.

Hemangiosarcomas of the adrenal gland, both benign and malignant, are exceedingly rare; only a dozen of them have been reported in literature to our knowledge. We describe herein the findings at CT of 2 primary hemangiosarcomas of the adrenal glands. We also discuss their etiology, incidence, and differential diagnosis, particularly in relation to more frequent primary adrenal lesions, such as adrenal adenomas and carcinomas. CT will generally show a heterogeneous mass with frequent necrosis, contrast-enhancement, and occasional calcifications. A prospective diagnosis cannot be made by imaging alone, and pathology represents the discriminating method for a correct diagnosis.

Primary effusion lymphomas in AIDS: CT findings in two cases.

Primary effusion lymphomas represent an unusual subset of AIDS-related non-Hodgkin's lymphomas. They are associated with herpes virus 8 and Epstein-Barr virus and characterized by predominant involvement of the serous body cavities (pleura, pericardium, peritoneum) as lymphomatous effusion without any identifiable tumour mass. We report herein CT findings in two patients with primary effusion lymphoma emphasizing the possible neoplastic nature of a pleural effusion in a patient with AIDS.

Peliosis hepatis with pseudotumoral and hemorrhagic evolution: CT and MR findings.

Peliosis hepatis is an uncommon benign disorder characterized by blood-filled cavities within the liver. We describe the sonographic, computed tomographic, and magnetic resonance appearance of a patient affected by peliosis hepatis with pseudotumoral and hemorrhagic evolution and direct demonstration of the ectatic vascular components.

Lipomatous tumors of the stomach: CT findings and differential diagnosis.

This article reviews the computed tomography imaging features of a variety of gastric tumors containing fatty tissue. Lipoma, angiolipoma, liposarcoma, and teratoma are described. Differential diagnosis includes primary and reactive lipomatosis, carcinoma engulfing the perivisceral fat thus mimicking differentiated liposarcoma, and mesenchymal gastric and peritoneal neoplasms.

[A magnetic resonance study of 39 children with different causes of short stature]. / Studio con Risonanza Magnetica di 39 bambini con differenti cause di bassa statura.

PURPOSE: To investigate the relationship between Magnetic Resonance (MR) findings and the presence of isolated growth hormone deficiency (IGHD) or multiple pituitary hormone deficiency (MPHD). MATERIAL AND METHODS: 39 children, 27 boys and 12 girls (mean age 9.6 years) were enrolled. The growth hormone deficiency and MPHD were defined by standard laboratory methods. MR scans of the hypothalamo-hypophyseal tract were carried out on all patients before the therapy. Perinatal histories were reviewed. RESULTS: The pituitary anterior lobe was considered small in 13/39 (33%). Twenty-six of 39 (66%) patients did not show any abnormalities of the hypothalamohypophyseal tract. An ectopic neurohypophysis was found in 8/39 patients (20%). Only 2 patients among those with an ectopic neurohypophysis showed a small anterior pituitary lobe. Thirty-three of 39 (84.6%) patients showed IGHD while 6/39 (15.4%) patients showed MPHD. Twenty-eight of 39 (71%) patients had a severe deficiency while 11/39 (28%) patients had a moderate deficiency. CONCLUSION: Our study confirms the usefulness of MRI in the diagnostic and therapeutic approach to short stature in children; in fact 48% of patients in our series showed MR findings reasonably related to hormonal deficiency.

Early spontaneous regression of a hypothalamic/chiasmatic mass in neurofibromatosis type 1: MR findings.

A patient with neurofibromatosis type 1 was found to have an enhancing mass in the hypothalamus and in the anterior optic pathway. A 3-month MR study showed a reduction in the size and enhancement of the mass. At a 9-month MR follow-up the mass disappeared and ceased to enhance. This report shows the unusual behaviour of a hypothalamic/chiasmatic mass confirming that in such asymptomatic cases the conservative management can be considered the treatment of choice.

Mesenchymal tumors of the pancreas: CT findings.

This article reviews the CT imaging features of the most frequent mesenchymal tumors of the pancreas and stresses important distinctive patterns that may help distinguish specific entities. Various neoplasms (lymphangioma, lipoma, teratoma, pancreatoblastoma, schwannoma, neurofibroma, lymphoma, and sarcoma) are reviewed, with key differential points (structure, fatty and water densities, calcification, pattern of contrast enhancement, vascularization, and necrotic or regressive changes) emphasized. In addition, epithelial tumors are considered in the differential diagnosis.