The IGF system in thyroid cancer: new concepts.

In recent years, the activation of the insulin-like growth factor (IGF) system in cancer has emerged as a key factor for tumour progression and resistance to apoptosis. Therefore, a variety of strategies have been developed to block the type I IGF receptor (IGF-I-R), which is thought to mediate the biological effects of both IGF-I and IGF-II. However, recent data suggest that the IGF signalling system is complex and that other receptors are involved. To unravel the complexity of the IGF system in thyroid cancer, IGF-I and IGF-II production, and the expression and function of their cognate receptors were studied. Both IGFs were found to be locally produced in thyroid cancer: IGF-I by stromal cells and IGF-II by malignant thyrocytes. Values were significantly higher in malignant tissue than in normal tissue. IGF-I-Rs were overexpressed in differentiated papillary carcinomas but not in poorly differentiated or undifferentiated tumours, whereas insulin receptors (IRs) were greatly overexpressed in all tumour hystotypes, with a trend for higher values in dedifferentiated tumours. As a consequence of IR overexpression, high amounts of IR/IGF-I-R hybrids (which bind IGF-I with high affinity) were present in all thyroid cancer histotypes. Because of recent evidence that isoform A of IR (IR-A) is a physiological receptor for IGF-II in fetal life, the relative abundance of IR-A in thyroid cancer was measured. Preliminary data indicate that overexpressed IRs mainly occur as IR-A in thyroid cancer. These data indicate that both IR/IGF-I-R hybrids and IR-A play an important role in the overactivation of the IGF system in thyroid cancer and in IGF-I mitogenic signalling in these tumours. J Clin PATHOL: Mol Pathol     

Angiogenesis in villous chorangiosis observed by ultrastructural studies

Chorangiosis is microscopically designated as more than ten terminal capillaries within the villous stroma of the placenta and is mostly related to chronic fetal hypoxia. However, the histogenetic relationship between increased number of terminal villous capillaries and chronic hypoxia has not yet been clarified. Of 665 placentas histologically examined at Saitama Medical University from 2003 to 2010, chorangiosis was found in 58 cases (8.7 %), which were mostly more than 35 gestational weeks. In addition, low birth weight (less than 2,500 g) infants (74.1 %) and those who suffered from cardiac anomalies, chromosome anomalies, and single umbilical artery comprised 32.7 % of cases. Placental lesions were associated with chorangiosis involved in infarct (46.6 %), intervillous thrombosis (20.7 %), and marginal hemorrhages (22.4 %). Scanning electron microscopic studies showed narrowing of vessel ostium and disorders of endothelium in the umbilical cord vessel complicated by chorangiosis. Furthermore, in transmission electron microscopic observation, not only the chorionic villi had multiple enlarged vessels within the villous stroma, but we also found that new capillaries were formed by angiogenesis with endothelial cells derived from fibroblasts under the chronic hypoxic state.     

Evolution of the subsolid pulmonary nodule: a retrospective study in patients with different neoplastic diseases in a nonscreening clinical context

Purpose

The aims of this study were to evaluate the high-resolution computed tomography (HRCT) features of subsolid pulmonary nodules (SSN) detected in cancer patients to differentiate between benign and malignant lesions, to assess their evolution during the follow-up, and to determine which neoplastic diseases are most frequently associated with the growth in size and/or density of SSN.

Materials and methods

Ninety-seven patients with a total of 146 subsolid nodules [140 pure ground-glass opacities (pGGOs) and six mixed ground-glass opacities (mGGOs)] were retrospectively recruited. Two chest radiologists independently reviewed the HRCT features of the nodules (location, shape, size, density) and the patients’ clinical characteristics (sex, age, smoking and cancer history). Mean duration of follow-up was more than 2 years.

Results

During follow-up, 58% of SSN remained stable, 10% disappeared. An increase in size and/or density was seen in 32% of SSN, and in particular in partly solid (mGGOs), large (≥10 mm) and irregular nodules. The majority of small-size (<5 mm) rounded SSN remained stable. SSN growth was more frequent in patients with advanced age and a history of smoking, and occurred even after a long period of stability (39% of pGGOs “changed” over 3 years). The neoplastic diseases most frequently associated with SSN growth were cancers of lung (34%), breast (15%), colon (15%) and bladder (10%).

Conclusions

The observation of a sample of cancer patients has shown that SSN may frequently grow in size and/or density in these patients, especially if associated powith cancers of lung, breast, colon and bladder. As the majority of SSN showed a very slow development time, a follow-up period longer than 3 years is warranted even in cancer patients.     

Natural history of honeycombing: follow-up of patients with idiopathic pulmonary fibrosis treated with single-lung transplantation

Purpose

Although honeycombing is one of the key features for the diagnosis of idiopathic pulmonary fibrosis (IPF), its origin and evolution are still poorly understood. The aim of our study was to analyse the natural history of honeycombing in patients treated with single-lung transplantation.

Materials and methods

We considered seven patients who underwent single-lung transplantation; two of them (28.6%) were excluded from our analysis because they died in the posttransplantation period, whereas the remaining five (71.4%) were evaluated with computed tomography (CT) over 67.6±38.56 months. Each CT scan was assessed for disease extension and cyst size (visual score and size of target cysts); CT scans acquired after 2006 were also assessed for native lung volume.

Results

All patients showed disease progression (with a concurrent reduction in lung volume in two, 40%) and a progression of honeycombing, with increased number and size of cysts in four (80%). We observed dimensional changes in all target cysts (enlargement or reduction); three patients (60%) also had radiological evidence of complications, such as spontaneous rupture with pneumothorax and development of mycetomas within the cysts.

Conclusions

Honeycombing is a dynamic process in which the overall trend is represented by a dimensional increase in cystic pattern; however, single cysts may have a different evolution (enlargement, reduction or complications). This behaviour could be explained by the variety of the pathogenetic processes underlying honeycombing, with cysts that may present abnormal communication with the airway, including the development of a check-valve mechanism.     

Molecular pathology in atherosclerosis: the mechanism by which cholesteryl ester accumulates in atheromatous aorta

To study how cholesterol accumulates in atheroma, novel monoclonal antibodies were developed, using crude homogenate of atheroma as immunogens. 212D monoclonal antibody recognizing extra cellular matrix with lipid-laden deposits was selected by histochemical staining. The antigen was deduced vitronectin from cDNA library. DLH3 monoclonal antibody recognizing oxidized LDL, epitope of which was 5- or 9-phosphatidylcholine. Significant correlations between oxidized LDL and coronary heart disease (CHD) patients were observed from clinical study. 256C monoclonal antibody recognizing atheromatous lesions in human aorta was selected. Epitope must be PC-cholesterol complex which may involve in foam cell rupture. Atherogenesis will be discussed from the aspects of these antibodies. Our working hypothesis is required to elucidate the mechanism. Denatured lipoproteins (either oxidized lipoprotein or ruptured foam cells) may induce atheroma. Oxidation of lipoprotein may be taken place both in foam cells and/or extra cellular matrix, and macrophage eliminate these denatured lipoproteins and become foam cells. The foam cells are ruptured by either apoptosis or necrosis afterward, and hydrophobic fragments of foam cells dispersed in extra cellular space, which destroys the function of biological membrane. Since biological function could be maintained by segregation of hydrophilic circumstances, macrophages uptake these fragmented material and oxidized lipoprotein to maintain the function. This vicious spiral may enhance chronically the atheroma.     

Acute myeloid leukemia with cryptic CBFB-MYH11 type D

A 77 year-old female was found with FAB M4Eo acute myeloid leukemia. Although CBFB-MYH11 mRNA was detected in RT-PCR, the conventional cytogenetic analysis failed to reveal inv(16). Fluorescence in situ hybridization (FISH) and the sequence analysis revealed a fusion between the exon 5 of CBFB and the exon 8 of MYH11, resulting in a minor variant fusion product previously reported as type D. In order to detect the cryptic inv(16) type D, both FISH and RT-PCR are required, and furthermore, the primers for the sequence analysis needs to be selected for the proper diagnosis.     

Open‐label,randomized, comparative,phase III study on effects of reducing steroid use in combination with Palonosetron

The purpose of this study is to compare the efficacy of a single administration of dexamethasone (DEX) on day 1 against DEX administration on days 1–3 in combination with palonosetron (PALO), a second-generation 5-HT3 receptor antagonist, for chemotherapy-induced nausea and vomiting (CINV) in non-anthracycline and cyclophosphamide (AC) moderately-emetogenic chemotherapy (MEC). This phase III trial was conducted with a multi-center, randomized, open-label, non-inferiority design. Patients who received non-AC MEC as an initial chemotherapy were randomly assigned to either a group administered PALO (0.75 mg, i.v.) and DEX (9.9 mg, i.v.) prior to chemotherapy (study treatment group), or a group administered additional DEX (8 mg, i.v. or p.o.) on days 2–3 (control group). The primary endpoint was complete response (CR) rate. The CR rate difference was estimated by logistic regression with allocation factors as covariates. The non-inferiority margin was set at −15% (study treatment group − control group). From April 2011 to March 2013, 305 patients who received non-AC MEC were randomly allocated to one of two study groups. Overall, the CR rate was 66.2% in the study treatment group (N = 151) and 63.6% in the control group (N = 154). PALO plus DEX day 1 was non-inferior to PALO plus DEX days 1–3 (difference, 2.5%; 95% confidence interval [CI]: −7.8%–12.8%; P-value for non-inferiority test = 0.0004). There were no differences between the two groups in terms of complete control rate (64.9 vs 61.7%) and total control rate (49.7% vs 47.4%). Anti-emetic DEX administration on days 2–3 may be eliminated when used in combination with PALO in patients receiving non-AC MEC.