The role of ultrasound-guided aspiration biopsy of peripheral pulmonary nodules: our experience

BACKGROUND: Peripheral lung lesions are difficult to diagnose with conventional methods: ultrasound-guided aspiration biopsy is an interesting prospect having been reported to have good sensitivity and specificity. PATIENTS AND METHODS: From January 1991 to August 2001 we investigated, in 268 patients, the role of ultrasound-guided transthoracic fine needle aspiration for cytological diagnosis of peripheral lung lesions. Nodule sizes ranged from 1 to 10 cm. RESULTS: From 268 patients, we obtained 174 positive specimens for malignancy, of which 155 were positive for primary lung tumors and 19 for metastasis; 76 negative; 9 inadequate; and 9 aspecific. One patient developed pneumothorax after needle aspiration and one patient emophtoe. The nodule size did not affect complication rate and diagnostic outcome. CONCLUSION: This diagnostic procedure appears to be effective, safe and feasible, even in bedridden patients. The cost is low (70Euro), the examination is fast (5-6 minutes) and well-tolerated and, if the specimen is inadequate or non-specific, it is possible to repeat the examination. Ultrasound-guided aspiration biopsy can replace the TC-guided biopsy in patients with peripheral lung nodules.     

Efficacy, tolerability and management of raltitrexed (Tomudex) monotherapy in patients with advanced colorectal cancer. a review of phase II/III trials

Raltitrexed (Tomudex), a thymidylate synthase inhibitor, is an alternative to 5-fluorouracil (5-FU)/leucovorin (LV) for the first-line treatment of advanced colorectal cancer. Following the completion of four phase III studies with raltitrexed at the recommended dose of 3.0 mg/m(2), it is opportune to review the efficacy and tolerability data of raltitrexed and suggest guidelines for appropriate patient management. Data are analysed from four phase III and five phase II studies including over 1300 patients with advanced colorectal cancer, some of whom were elderly or received higher doses of raltitrexed. Median survival with raltitrexed was comparable to that of bolus or infusional 5-FU/LV in three of the four randomised studies and objective response rates in the four trials were similar for the two agents. Response rates were at least comparable in elderly patients in phase II studies. For the majority of patients, treatment with raltitrexed was well tolerated even at doses higher than that recommended or in the elderly. As with other cytotoxic agents, serious and potentially life-threatening side-effects can occur; nevertheless, adherence to simple patient guidelines should minimise the incidence of serious side-effects with raltitrexed; these include the assessment of renal function before each and every treatment, dosage adjustment in the presence of renal impairment and close monitoring with prompt treatment of toxicities, particularly diarrhoea and neutropenia.     

Alternation of epirubicin and mitoxantrone in CHOP-like regimens retains efficacy and reduces overall toxicity in elderly patients with high and intermediate grade non-Hodgkin lymphomas

Mitoxantrone and Epirubicin are active agents in non-Hodgkin's lymphomas (NHL). These drugs have reduced cardiotoxicity and therefore are indicated in treatment of elderly patients. Cyclophosphamide, mitoxantrone, vincristine and methylprednisone (CNOP) and cyclophosphamide, epirubicin, vincristine and methylprednisone (CEOP) are combination chemotherapy and contain Mitoxantrone and Epirubicin that have been shown to be effective in treatment of NHL of intermediate and highgrade of malignancy in the elderly. Since Mitoxantrone and Epirubicin are partially non-cross resistant their combined use may diminish emergence of resistant neoplastic clones and may be associated with enhanced anti-neoplastic activity. In this study, a polychemotherapy schedule alternating 3 cycles of CEOP and 3 cycles of CNOP, was used in a single center between December 1988 and April 1995 to treat 41 previously untreated patients, over 60 years of age affected by intermediate or high grade non-Hodgkin's lymphoma according to the Working Formulation. In treated patients, 57.5% achieved complete response, 35% partial response and 7.5% were non-responders. Overall survival was 52.4 % at 4 years, Disease free survival (DFS) for complete responders was 48.9%. Only one case of severe extrahematological toxicity (grade 3-4 WHO) was observed. Severe mucositis (grade 3-4 WHO) was absent, and delayed administration of chemotherapy was required in only 7/230 cycles. No treatment related deaths were registered. This regimen achieved results comparable to that of other anthracycline or mitoxantrone based chemotherapy, but determined lower toxicity. Alternating CEOP and CNOP may improve overall toxicity.     

Clinical and dermatoscopic diagnosis of small pigmented skin lesions

Small pigmented skin lesions represent a new challenge for all physicians devoted to the early diagnosis of melanoma. The purpose of this prospective study was to establish the diagnostic value of the clinical and the dermatoscopic examinations in a population of 157 consecutive patients with 161 small (< or = 6 mm) pigmented lesions, recruited in a short time. Of these 161 lesions, 13 were thin melanomas (median thickness 0.49 mm). In this population, clinical evaluation produced a diagnostic sensitivity of 77% and a specificity of 74%. Dermatoscopy resulted in a sensitivity of 77% and in a specificity of 72%. Combining clinical and dermatoscopic evaluations all the melanomas were preoperatively recognised. The results of the present study stress the complementary role of clinical and dermatoscopic examinations. In particular, clinical evaluation remains of utmost importance in diagnosing melanoma. This concept must be stressed in the education and training of young dermatologists.     

Study of formulation variables influencing the drug release rate from matrix tablets by experimental design.

Experimental design was utilized to simultaneously investigate the effect of varying the type of diluent (insoluble Calcium phosphate or water-soluble arabic gum) and the diluent/matrix ratio on the drug release behaviour from both lipophilic (glyceryl behenate, Compritol) or hydrophilic (hydroxypropylmethylcellulose) matrix tablets. Ketoprofen, theophylline and sodium sulphadiazine were selected as model drugs on the basis of their respectively very low, medium and high water-solubility, in order to evaluate the influence of this parameter as well. The selected response variables were the dissolution efficiency (i.e. the area under the dissolution curve) after one and six hours and the time necessary to dissolve 10% drug. Tablets obtained by direct compression of drug-diluent-matrix ternary mixtures prepared according to the experimental plan provided for by an asymmetric screening matrix, were tested for drug release properties using a USP paddle apparatus. Graphic analysis of the effects allowed identification, for each examined drug, of the formulation factors active on the selected responses and determination of the proper level of the variables to be selected for the response improvement. The different results obtained with the three examined drugs pointed out the role of the drug solubility in determining the influence of formulation parameters on drug release rate from matrix tablets.     

Phase I-II study of gemcitabine and paclitaxel in pretreated patients with stage IIIB-IV non-small cell lung cancer

Gemcitabine and paclitaxel are among the most active new agents in non-small cell lung cancer (NSCLC) and are worth considering for second-line chemotherapy. In this phase I–II study, we combined gemcitabine and paclitaxel for second-line treatment of advanced NSCLC. Gemcitabine doses were kept fixed at 1000 mg/m² on day 1 and 8, and paclitaxel doses were escalated from 90 mg/m² on day 1 of the 21-day cycle. Thirty-seven patients were treated at six different dose levels. Grade 4 neutropenia was dose-limiting toxicity (DLT), since it occurred in two out of six patients treated at paclitaxel 240 mg/m²; the paclitaxel dose level just below (210 mg/m²) was selected for phase II evaluation. Non-hematologic toxicity was mild. One complete response (CR) (3%) and 13 partial responses (PR) (36%) were observed in 36 evaluable patients for an overall response rate of 39% (95% C.I., 23–57%). Median duration of response was 35 weeks (range, 8–102). All of the observed objective responses occurred in the 19 patients who had previously responded to the first-line therapy. Median survival was 40 weeks (range, 8–108 weeks). The combination of gemcitabine and paclitaxel is a feasible, well-tolerated, and active scheme for second-line treatment of advanced NSCLC; further evaluation, at least in selected patients, such as those previously responding to first-line chemotherapy, is definitely warranted.     

Morphometric study of collagen maturation in chick compact bone

An ultrastructural-morphometric study was carried out on the process of osteoid maturation in growing surfaces of parallel-fibered chick bone. The aim was to investigate the distribution, size and amount of collagen fibrils (CFs), as well as the proteoglycan (PG) content, throughout the osteoid seam and in the adjacent bone. The results show that the organic components secreted by osteoblasts undergo complete maturation inside the osteoid seam only. Proceeding from the secreting plasma membrane of osteoblasts (osteoidogenic surface) towards the mineralizing surface, we found that CFs gradually increase in diameter but not in number per surface unit. As a consequence, the proportion of osteoid seam occupied by CF increases too, at the expense of the interfibrillar substance. PG content also decreases inversely in this direction. In the adjacent bone, CF size and density do not change significantly with respect to the mature osteoid close to the mineralizing surface.     

Dose and volume as predictive factors of pulmonary toxicity

Dose and volume and their correlation with the development of pulmonary toxicity are among the most widely studied and validated factors in radiotherapy. Most common treatment planning systems allow prompt assessment of Vdose and Mean Lung Dose (MLD). The former represents the percentage of normal lung parenchyma receiving a dose equal to or higher than the established threshold dose; the latter corresponds to the mean dose delivered to the normal lung parenchyma. Most important studies reported on the subject and threhold values recommended for Vdose and MLD are analyzed. The monitoring system of late toxicity used by the authors is presented.     

DNA fragmentation and DNA repair synthesis induced in rat and human thyroid cells by four rat thyroid carcinogens

Four chemicals that are known to induce in rats thyroid follicular-cell adenomas and carcinomas were assayed for their ability to induce DNA damage and DNA repair synthesis in primary cultures of human thyroid cells. Significant dose-dependent increases in the frequency of DNA single-strand breaks and alkali-labile sites, as measures by the Comet assay, were obtained after a 20-h exposure to the following subtoxic concentrations of the four test compounds: 2,4-diaminoanisole (DAA) from 0.10 to 1.0 mM, 4,4'-methylene-bis(N,N-dimethyl)benzenamine (MDB) from 0.32 to 1.8 mM, propylthiouracil (PTU) from 1.8 to 5.6 mM, and 4,4'-thiodianiline (THA) from 0.032 to 0.18 mM. Under the same experimental conditions, DNA repair synthesis, as evaluated by quantitative autoradiography, was present in thyreocytes exposed to DAA but absent after treatment with MDB, PTU, and THA. Consistent with their thyroid-specific carcinogenic activity, all the four chemicals, administered p.o. in rats in a single dose corresponding to 1/2 LD50, induced a statistically significant degree of DNA fragmentation in the thyroid, whereas any substantial evidence of DNA lesions was absent in liver, kidney, and lung, which, with the exception of liver tumors caused by THA, are not targets of the carcinogenic activity of the four test compounds. These findings indicate that the DNA damage observed in thyroid cells was consistent with the carcinogenicity of the four test compounds, and suggest that DAA, MDB, PTU, and THA might be carcinogenic to thyroid in humans.     

Analysis of morphologic patterns of fine-needle aspiration of the breast to reduce false-negative results in breast cytology

BACKGROUND: The identification of specific morphologic diagnostic criteria is of paramount importance to optimize the accuracy of fine-needle aspiration cytology (FNAC) and to reduce the rate of false-negative results. In the current study, the authors reviewed a consecutive series of false-negative findings observed in the study center to define the presence and degree of cytologic abnormalities. False-negative cases were randomly mixed with true-negative cases and were reviewed by a panel of expert readers in a blinded fashion. The main objective of the current study was to identify a morphologic pattern that may permit the reduction of false-negative findings while maintaining the specificity of FNAC. METHODS: A blind review of a set of 41 consecutive false-negative and 49 true-negative breast aspiration samples was performed by a panel of 10 expert cytologists who were asked to give a final report and to classify the samples according to classic morphologic parameters. RESULTS: The majority final report sensitivity was 54% (range, 19-61%) and specificity was 73% (range, 65-92%). The average concordance with the majority report, adjusted for chance agreement (kappa statistic), was moderate at 0.54 (range, 0.40-0.65). Enlarged nuclear size, a hyperchromatic nucleus, the absence of naked nuclei, and the absence of apocrine metaplasia were reported more frequently in carcinoma cases, although not to a significant extent. The only variable found to be associated significantly (P = 0.041) with a diagnosis of carcinoma was the presence of microcalcifications, which nevertheless were found to occur in only a minority of carcinoma cases (7 of 41 cases) or controls (2 of 49 controls). Multivariate analysis demonstrated that the presence of microcalcifications (odds ration [OR] of 3.0; 95% confidence interval [95% CI], 1.2-7.4), the absence of naked nuclei (OR of 2.4; 95% CI, 1.3-4.4), and enlargement of the nucleus (OR of 1.9; 95% CI, 1.1-3.4) were all independently associated with false-negative findings. Diagnostic accuracy using a morphology-based score did not appear to improve the results substantially compared with the final report (sensitivity of 0.46 vs. 0.54 [P = 0.508] and a specificity of 0.80 vs. 0.73 [P = 0.218]). CONCLUSIONS: The results of the current study confirm that breast FNAC false-negative results are at least partially the result of underreporting of abnormalities that may be noted at review. Detailed analysis of a single morphologic characteristic was found to be of limited diagnostic value, suggesting that operators do perceive abnormalities but cannot translate these findings into distinct morphologic categories.