Factors predicting radiation pneumonitis in lung cancer patients: a retrospective study.

PURPOSE: To evaluate clinical and lung dose-volume histogram based factors as predictors of radiation pneumonitis (RP) in lung cancer patients (PTs) treated with thoracic irradiation. METHODS AND MATERIALS: Records of all lung cancer PTs irradiated at our Institution between 1994 and 2000 were retrospectively reviewed. Eighty-four PTs with small or non-small-cell lung cancer, irradiated at >40 Gy, with full 3D dosimetry data and a follow-up time of >6 months from start of treatment, were analysed for RP. Pneumonitis was scored on the basis of SWOG toxicity criteria and was considered a complication when grade> or =II. The following clinical parameters were considered: gender, age, surgery, chemotherapy agents, presence of chronic obstructive pulmonary disease (COPD), performance status. Dosimetric factors including prescribed dose (Diso), presence of final conformal boost, mean lung dose (Dmean), % of lung receiving > or =20, 25, 30, 35, 40, and 45 Gy (respectively V20-->V45), and normal tissue complication probability (NTCP) values were analysed. DVHs data and NTCP values were collected for both lungs considered as a paired organ. Median and quartile values were taken as cut-off for statistical analysis. Factors that influenced RP were assessed by univariate (log-rank) and multivariate analyses (Cox hazard model). RESULTS: There were 14 PTs (16.6%) who had > or =grade II pulmonary toxicity. In the entire population, the univariate analysis revealed that many dosimetric parameters (Diso, V20, V30, V40, V45) were significantly associated with RP. No significant correlation was found between the incidence of RP and Dmean or NTCP values. Multivariate analysis revealed that the use of mitomycin (MMC) (P=0.005) and the presence of COPD (P=0.026) were the most important risk factor for RP. In the group without COPD (55 PTs, seven RP) a few dosimetric factors (Dmean, V20, V45) and NTCP values (all models) were associated with RP in the univariate analysis (P< or =0.06). According to the multivariate analysis, the use of MMC was independently associated with RP (P=0.007), while Dmean approached statistical significance (P=0.082). CONCLUSIONS: In this study the use of mitomycin or the presence of COPD is associated with a higher risk of RP. In the entire population NTCP values were not significantly correlated with the incidence of RP. Mean lung dose shows a clear trend toward statistical significance in the patient group without COPD.     

Phase II study of weekly paclitaxel as second-line therapy in patients with advanced non-small cell lung cancer

A growing number of patients, mainly cisplatin-pretreated, require second-line therapy for non-small cell lung cancer (NSCLC) but the optimal treatment and appropriate criteria for patient selection have not been defined yet. A second-line phase II study was conducted in cisplatin-pretreated patients with advanced NSCLC to evaluate the activity and toxicity of weekly paclitaxel. Fifty-three consecutive NSCLC patients (9 stage IIIA-B, 44 stage IV) progressing after one front line cisplatin-based chemotherapy were enrolled. Previous treatment with taxanes was not allowed. Patients with stage III were also pretreated with thoracic radiotherapy. Weekly paclitaxel was administered as 1-h infusion at a dose of 80 mg/m(2) for three weeks with one week off, for a maximum of four courses. All patients were assessable for response, toxicity and survival. A complete response was observed in one case, partial response in 7, for an overall response rate (RR) of 15%, (95% Cl = 5-25%). Stable disease (SD) was registered in 11 patients, for an overall clinical benefit (CB = RR + SD) of 36% (95% Cl = 23-49%). Toxicity was mild, with G3-4 neutropenia and thrombocytopenia in 6 and 2% of patients, respectively. Non-hematological toxicities were negligible. No significant correlation between patient or treatment-related variable and RR was observed. CB was significantly higher in patients with non-squamous histology (P = 0.03) and no progression within 4 months of first line cisplatin-based chemotherapy (P = 0.007). Median progression-free survival (PFS) was 7 months in responders and 4 months in pts with SD. PFS was significantly related to good performance status (PS) (P = 0.002) and non-squamous histology (P = 0.004). In conclusion, weekly paclitaxel has acceptable palliative activity and excellent tolerance in cisplatin-pretreated patients. Patients with PS 0-1, non-squamous histology and with no progression within 4 months of first line cisplatin-based chemotherapy seem more likely to benefit from this treatment.     

Role of hypoxia-inducible factor-1α in angiogenic–osteogenic coupling

Angiogenesis and osteogenesis are tightly coupled during bone development and regeneration. The vasculature supplies oxygen to developing and regenerating bone and also delivers critical signals to the stroma that stimulate mesenchymal cell specification to promote bone formation. Recent studies suggest that the hypoxia-inducible factors (HIFs) are required for the initiation of the angiogenic–osteogenic cascade. Genetic manipulation of individual components of the HIF/vascular endothelial growth factor (VEGF) pathway in mice has provided clues to how coupling is achieved. In this article, we review the current understanding of the cellular and molecular mechanisms responsible for angiogenic–osteogenic coupling. We also briefly discuss the therapeutic manipulation of HIF and VEGF in skeletal repair. Such discoveries suggest promising approaches for the development of novel therapies to improve bone accretion and repair.     

Partial rescue of PTH/PTHrP receptor knockout mice by targeted expression of the Jansen transgene.

The homozygous ablation of the gene encoding the PTH/PTHrP receptor (PPR(-/-)) leads to early lethality and limited developmental defects, including an acceleration of chondrocyte differentiation. In contrast to the findings in homozygous PTHrP-ablated (PTHrP(-/-)) animals, these PPR(-/-) mice show an increase in cortical bone, a decrease in trabecular bone, and a defect in bone mineralization. Opposite observations are made in Jansen's metaphyseal chondrodysplasia, a disorder caused by constitutively active PPR mutants, and in transgenic animals expressing one of these receptor mutants (HKrk-H223R) under control of the type alpha1(I) collagen promoter. Expression of the Jansen transgene under the control of the type alpha1(II) collagen promoter was, furthermore, shown to delay chondrocyte differentiation and to prevent the dramatic acceleration of chondrocyte differentiation in PTHrP(-/-) mice, thus rescuing the early lethality of these animals. In the present study we demonstrated that the type alpha1(II) collagen promoter Jansen transgene restored most of the bone abnormalities in PPR(-/-) mice, but did not prevent their perinatal lethality. These findings suggested that factors other than impaired gas exchange due to an abnormal rib cage contribute to the early death of PPR(-/-) mice.     

Giardia lamblia infection in patients with irritable bowel syndrome and dyspepsia： A prospective study

AIM:To evaluate the prevalence of Giardia lamblia(G.lamblia)infection in patients with irritable bowel syndrome(IBS)and dyspepsia and to establish which is the mostaccurate test to diagnose the infection in this setting.METHODS:One hundred and thirty-seven patients whoconsecutively attended the Outpatient GastroenterologyClinic for the first time between January 2002 and De-cember 2003 due to symptoms of IBS and/or dyspepsiawere recruited.All patients underwent clinical evaluation,first-step haematology and chemistry tests,serologic as-says for celiac disease,lactose-H2 breath test,abdominalultrasonography,and esophagogastroduodenoscopy.Helicobacter pylori status was evaluated.In patients withsymptoms of IBS older than 45 years,colonoscopy wasalso performed.In all patients,duodenal biopsies andstool samples were examined for trophozoites and cystsof G.lamblia by several methods.RESULTS:G.lamblia was identified in 9 patients.Thefollowing diagnoses were also made:IBS(100/137,73%),functional dyspepsia(62/137,45%),organicdyspepsia(33/137,24%),and lactose intolerance(75/137,55%).A significant association was foundbetween giardiasis and H pylori infection(X~2=6.632,OR=12.4,CI=1.5-68.1).There were no symptomsthat reliably allowed the recognition of giardiasis.Direct search of the parasite in duodenal biopsy andstool sample examinations gave concordant results inall cases while histological examination of duodenal biopsies displayed a low sensitivity(e.g.,22.2%).CONCLUSION:In this consecutive series,diagnosisof G.lamblia infection accounted for 6.5% of patientswith IBS and dyspepsia.Duodenal biopsies for diag-nosis of giardiasis may be unnecessary if stool sampleexamination is performed.     

PTH and stem cells

At least 2 different types of cells, hematopoietic and mesenchymal, are present in the adult bone marrow, in addition to endothelial cells. Hematopoietic and mesenchymal cells are believed to originate from hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC), respectively. The bone marrow stroma, a cellular microenvironment that supports HSC, is composed of non-hematopoietic cells and contains MSC. A unique expansion of the bone marrow stroma, also known as marrow fibrosis, is the hallmark of a variety of disorders including hyperparathyroidism and fibrous dysplasia. PTH is the first bone anabolic agent approved by US Food and Drug Administration for the treatment of osteoporosis. Recent studies have suggested that PTH treatment may affect the number of hematopoietic stem cells in the bone marrow and their mobilization into the bloodstream. In addition, cells with classical features of mesenchymal stem cells/progenitors have been shown to express receptors for PTH, and to increase in number and undergo redistribution in the adult bone marrow upon PTH treatment. In this review, we will summarize the up-to-date knowledge on PTH and its relation to stem cells. We will also discuss the contribution of different cell types to the development of marrow fibrosis and the involvement of PTH signaling in this pathology.     

Hardness of plantar skin in diabetic neuropathic feet.

To evaluate if skin hardness in diabetic neuropathic feet was increased and if its eventual modifications could be correlated to the severity of neuropathy, we studied a group of diabetic outpatients with and without neuropathy. Patients, selected among those who were attending their routine screening for diabetic neuropathy at our diabetologic clinic, were divided into two groups according to the presence (ND+) or absence (ND-) of diabetic neuropathy with the criteria of the S. Antonio Consensus Conference on Diabetic Neuropathy. Patients then underwent an evaluation of vibration perception threshold (VPT) by means of a biotesiometer, measurement of skin hardness (DMT) by means of a durometer, and transcutaneous oxygen tension (TcPO2) determination. VPT was determined at allux (VPT-A) and external malleolus (VPT-M), DMT was measured at heel (DMT-H), at medial (DMT-M) and lateral (DMT-L) midfoot, and at posterior midcalf (DTM-C) as a control site; TcPO2 was evaluated at dorsum (TcPO2-D) and at medial midfoot (TcPO2-M), respectively. All measurements were performed on the nondominant side with the patients supine. Patients were compared with age and gender-matched healthy volunteers (Controls), who underwent the same evaluations in the same order. ND+ patients showed higher values of VPT than ND- and Controls, both at first toe and at malleolus analysis of variance (ANOVA) p<0.01), as well of DMT in all the three sites explored (ANOVA, p<0.01). Moreover, ND+ showed no difference in DMT among the sites, while both in ND- and in controls DMT-M was significantly (p<0.05) lower than DMT-H and DMT-L. No difference among the three groups were observed in TcPO2 measurements, and no difference in DMT-C was observed either. A significant correlation was observed between DMT-H and VPT-M (r2 = 0.516) and between DMT-M and VPT-A (r2 = 0.624) in ND+ patients. Skin hardness was diffusely increased in ND+ patients, and this increase strongly correlates with the severity of neuropathy. Simple, noninvasive determination of skin hardness could identify patient at potential risk to develop neuropathic foot ulcers.     

CO2 laser and photodynamic therapy: Study of efficacy in periocular BCC

Basal cell carcinoma (BCC), the most common type of skin cancer in the world, usually arises in sun‐exposed areas of the skin. The therapeutic approach to periocular BCC has changed in the last few years. Currently the treatment, considering the delicate localization of the disease, must not only ensure complete recovery from the neoplastic disease, but must also satisfy functional and aesthetic criteria. In this study we tried to evaluate the efficacy of CO₂ laser and photodynamic therapy in periocular BCC.