Karyotype-phenotype correlation in partial trisomies of the short arm of chromosome 6: a family case report and review of the literature.

The first child (proband) of nonconsanguineous Caucasian parents underwent genetic investigation because she was affected with congenital choanal atresia, heart defects and kidney hyposplasia with mild transient renal insufficiency. The direct DNA sequencing after PCR of the CHD7 gene, which is thought to be responsible for approximately 60-70% of the cases of CHARGE syndrome/association, found no mutations. The cytogenetic analysis (standard GTG banding karyotype) revealed the presence of extrachromosomal material on 10q. The chromosome analysis was completed with array CGH (30 kb resolution), MLPA and FISH, which allowed the identification of three 6p regions (6p.25.3p23 × 3): 2 of these regions are normally located on chromosome 6, and the third region is translocated to the long arm of chromosome 10. The same chromosomal rearrangement was subsequently found in the father, who was affected with congenital ptosis and progressive hearing loss, and in the proband's sister, the second child, who presented at birth with choanal atresia and congenital heart defects. The mutated karyotypes, which were directly inherited, are thought to be responsible for a variable phenotype, including craniofacial dysmorphisms, choanal atresia, congenital ptosis, sensorineural hearing loss, heart defects, developmental delay, and renal dysfunction. Nevertheless, to achieve a complete audiological assessment of the father, he underwent further investigation that revealed an increased level of the coagulation factor XIII (300% increased activity), fluctuating levels of fibrin D-dimer degradation products (from 296 to 1,587 ng/ml) and a homoplasmic mitochondrial DNA mutation: T961G in the MTRNR1 (12S rRNA) gene. He was made a candidate for cochlear implantation. Preoperative high-resolution computed tomography and magnetic resonance imaging of the temporal bone revealed the presence of an Arnold-Chiari malformation type I. To the best of our knowledge, this study is the second report on partial 6p trisomy that involves the 10q terminal region. Furthermore, we report the first case of documented Arnold-Chiari malformation type I and increased factor XIII activity associated with 6p trisomy. We present a comprehensive report of the familial cases and an exhaustive literature review.

RNA interference against urokinase in hepatocellular carcinoma xenografts in nude mice.

The serine protease urokinase-type plasminogen activator (u-PA) is overexpressed in hepatocellular carcinoma (HCC) and its expression level is inversely correlated with the patients' survival. The purpose of this study was to examine the effects of vector-based RNA interference (RNAi) of u-PA on the growth of human HCC xenografts in nude mice in order to investigate the role of u-PA in human HCC. Our results showed that the subcutaneous injection of small interfering RNAs (siRNA) u-PA SKHep1C3 stable transfected cells (pS siRNA u-PA) led to a growth delay in xenograft development, compared to those generated from empty vector; the molecular characterization of nodules (carried out by PCR, RT-PCR and immunohistochemical analysis) revealed the presence of plasmid DNA, the u-PA gene expression knockdown, at both mRNA and protein levels, giving evidence of a long-term and target-specific inhibition by vector-based RNAi 11 weeks after cell inoculation. We further studied the effects of u-PA down modulation on extracellular matrix (ECM) proteins evaluating the expression and organization of fibronectin (FN; one of the main ECM proteins). Immunohistochemical and immunofluorescence analysis of FN revealed FN fibrils in pS siRNA u-PA xenografts and in pS siRNA u-PA cells, thus identifying the FN fibril organization as a downstream effect of u-PA knockdown in this system.

Paclitaxel, ifosfamide, and carboplatin for the treatment of stages IIIB and IV non-small cell lung cancer: preliminary results.

We have treated 26 consecutive chemotherapy-naive patients with stage IIIB/IV non-small cell lung cancer with an innovative regimen based on a 1-hour infusion of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 125 to 250 mg/m2, ifosfamide 3 g/m2 (with mesna), and carboplatin dosed to an area under the concentration-time curve of 5, every 21 days for a total of six cycles in responding or stabilized patients. Among 22 fully evaluable patients, 14 (64%) achieved a partial remission, six had disease stabilization, and two had disease progression. Hematologic toxicity was remarkably mild; only one patient had grade 3 neutropenia (on day 21). Arthralgias/myalgias (grade 3 in nine patients, grade 4 in one patient) and neurologic toxicity (a cumulative sensory neuropathy of grade 3 or 4 in five patients) were the most common side effects and seem to be dose related. To date, few patients are fully evaluable and survival data are clearly immature. Nevertheless, this regimen seems highly active and quite well tolerated, and deserves further evaluation.

[The current indications for Madden's radical mastectomy in our experience. A critical review of 201 consecutive patients]. / Attuali indicazioni alla mastectomia radicale secondo Madden nella nostra esperienza. Revisione critica in 201 pazienti consecutive.

The clinical pathological data regarding the 201 patients (203 operations running) who underwent radical mastectomy according to Madden in the II Division of General Surgery at Brescia Civil Hospital in the period 1993-1994, have been reexamined in order to check the real need of radical surgery. This further analysis, apart from the patients with neoplasias of considerable dimensions (T2; > 2 cm), has been carried out on 100 tumors smaller dimensions (T1; < 2 cm) and has confirmed the necessity of radical surgery in 87 cases. Of the 13 operations (6.4%) that have been considered "improper" 2 were due to erroneous clinical staging (dubious cutaneous infiltration) and 5 (2.5%) presented a neoplastic diameter of exactly 2 cm which only partially justified radical surgery. In six patients (2.9%) we haven't found clinical pathological elements which contraindicated conservative surgery.

Mitomycin-C and lonidamine as second-line therapy for colorectal cancer: a phase II study.

AIMS AND BACKGROUND: Recent preclinical data have suggested that lonidamine may potentiate the acitivity of mitomycin C in human colon cancer cell lines LoVo and HT29. STUDY DESIGN: A phase II study was carried out in 14 patients with advanced colorectal cancer pretreated with fluorouracil and folinic acid. Treatment consisted of lonidamine, 600 mg po, followed after 2 h by mitomycin, 20 mg/m2 by iv bolus, followed by lonidamine, 150 mg tio for 5 days; the cycle was repeated every 6 weeks. RESULTS: No objective response was seen. Three patients had stable disease; the median survival for the whole group was 4 months. Although hematologic toxicity was negligible, lonidamine-related side effects were moderate to severe in most patients and mainly represented by myalgia and gastric pain. DISCUSSION: Despite a sound preclinical rationale, this schedule of lonidamine and mitomycin C was ineffective and toxic in patients with advanced colorectal cancer. More experimental data about lonidamine are needed in order to design more effective regimens based on the combination of this interesting drug with other anticancer agents.

5-fluorouracil by protracted subcutaneous infusion. A pilot study.

A feasibility study of 5-fluorouracil (5-FU) delivered by long-term subcutaneous infusion (SCI) was carried out in 10 patients with advanced malignancies refractory to conventional treatment. 5-FU: 200 mg/m2/day was administered by an external infusor (Baxter 5 or 7 Multiday) connected with a 21-gauge needle placed in the thoracic wall. Treatment was continued until progression of disease or toxicity. WHO grade II to III mucositis was experienced by two and one patients, respectively. Grade II diarrhea developed in one patient. Local toxicity was substantial but painless and manageable; skin ulceration was experienced by two patients. A total of 88 weeks of therapy was delivered with a median of 8.8 weeks for each patient (range 2 to 16). Two patients (breast and colorectal cancer) achieved a partial remission; two additional cases showed a > 50% decrease in tumor marker levels. In conclusion, the administration of 5-FU by SCI deserves further evaluation, especially in clinical circumstances in which venous access is limited by thrombosis or technical concerns.

Complications of plasma-exchange.

Complications in apheresis affect on the average 40% of treated patients and 10-14% of the procedures. The mortality rate is 1/500 treated patients. The utilization of more complex techniques, central catheters, plasma infusion and even more the superimposition of different factors increase the incidence and gravity of side effects. Very influent are also the underlying pathologies and the clinical conditions; particularly at risk are patients with TTP/HUS and GBS. However, PE represents a relatively safe therapy in which prevention of complications requires a particularly diligent personnel and a careful evaluation of indications.

Apheresis and biocompatibility: complement activation.

When blood comes into contact with plastic surfaces of extracorporeal circuits activation of different biological systems occurs, among them the complement. This will be activated mainly through the alternative pathway but also through the classical one. The activation through the latter pathway occurs when antibodies directed against polymeric materials used for the production of extracorporeal circuits or substances utilized for their sterilization are produced by the patient's immunosystem. Even if complement activation occurs almost constantly during apheretic procedures the natural inhibitory mechanisms of this system attenuate and disguise this phenomenon. Important and clinical manifestations occur in particular patients or in case of technologically more complex techniques. In apheresis the complement activation may be implicated in the relatively frequent complications such as fever and chills, hypotension, as well as in the rare but severe cases of ARDS.

Breast cancer screening in an urban population in northern Italy.

A mammographic and clinical screening for breast cancer started in June 1987 in the Health District of Brescia, Northern Italy, including the town and 23 surrounding municipalities. This paper describes the organization and the results of the first 12 months of screening. Of 7791 invited women aged 50-60 years, 5217 (67%) agreed to participate. There was a trend for response rates to decline with increasing age and education. Of the 5217 women examined, 66 (1.3%) were referred for biopsy and 64 (1.2%) underwent this procedure. A histologically confirmed malignancy was found in 42 women, corresponding to a prevalence of 8.1/1000. Positive predictive value of the screening was 65.6%. Among the 42 breast cancers, 4.8% were carcinoma in situ and 42.9% invasive tumors up to 10 mm in size. According to the p-TNM classification, 92.9% of all cancers were either TIS or in stage T1, 4.8% were in T2 and one tumor was classified in T4. Lymph node involvement was assessed in 41 cases, and 71.4% of all cancers detected by screening were negative for lymph node metastasis. In comparison, the classification of tumors found in women of the same age group and living in Brescia, histologically diagnosed in the urban hospitals during 1986, one year before the beginning of the screening, was as follows: 7.1% carcinoma in situ, and 16.7% invasive tumors up to 10 mm in size. 38.1%, 2.4% and 2.4% of all tumors were in stages T2, T3 and T4 respectively.

Carcinoma of the gastric stump following partial gastrectomy (Billroth II operation) for benign gastroduodenal lesions. Preliminary results.

A series of 110 patients out of 2,200, who had undergone Billroth II partial gastrectomy for benign lesions, between 1945 and 1980, was reviewed in order to perform clinical, biochemical and endoscopical examinations. In this group 9 patients (8.18%) showed gastric stump cancer and in 4 (3.63%) esophageal cancer was detected. The average time interval between previous operation and carcinoma diagnosis was of 28 years and 6 months. Eight patients out of 9 were males aging from 47 to 82, while the only woman was 65 (overall average: 63). The stump cancer presents at the same age and gives the same symptoms as primitive gastric carcinoma, but with worse results and prognosis. After having underlined some pathogenetic problems, the Authors show personal results and confirm the utility of an accurate endoscopical and clinical follow up especially for patients operated on since more than twenty years.

Relationship of serum lactate dehydrogenase level with first remission length in adult acute lymphocytic leukaemia.

Several features have a prognostic value in adults with acute lymphocytic leukaemia (ALL). However, in about two-thirds of all cases prognosis remains quite variable, with a substantial number of early relapses. This study shows in 118 adult patients who attained complete remission (CR) between 1978 and 1984 that pretreatment serum total lactate dehydrogenase (LDH) activity was inversely correlated with first CR length. The prognostic value of LDH was higher than that of any other features both in univariable and in multivariable analysis. The value was significant in the whole series as well as in patients who lacked other high risk features. Among non-high risk and low-WBC count cases, patients with LDH less than or equal to 500 U/l had a median first CR duration of 27 months, and a projected 5-year relapse free survival of 36%, versus 9 months and 12% of patients with LDH greater than 500 U/l. These results fit well with the results of a study of ALL in children, and suggest that pretreatment serum total LDH activity is an important risk determinant in adult ALL.

Estrogen and progesterone receptors in neoplastic cells of metastatic pleural effusion of breast carcinoma before and after tamoxifen therapy. Correlation with the clinical response.

We have investigated the activity of tamoxifen in 12 post-menopause patients affected by advanced breast carcinoma and, in this specific case, by metastatic pleural effusion. A receptor assay was carried out on all patients to assess the estrogen and progesterone receptor activity in pleural effusion tumor cells, cytologically confirmed. The assay was performed both at the moment of the diagnostic check and after a week of 30 mg/die of tamoxifen therapy. We obtained a temporary reduction of the pleural effusion in 5 patients out of 12 (42%). Four out of these 5 patients presented estrogen receptors (ER+) at the first assay. In the 4 patients with negative receptors (ER-) neither a decrease of the percentage of tumoral cells, nor a reduction of the effusion was ascertained. This study shows that also for pleural effusions tamoxifen's therapeutic benefit was obtainable only in those patients with estrogen receptors in the tumoral cells.

Decrease of granulocyte-macrophage colony-forming units during high dose medroxyprogesterone acetate treatment in advanced breast cancer.

We treated 18 post-menopausal women with advanced breast cancer with medroxyprogesterone-acetate 1000 mg p.o. daily. The study of granulocyte-macrophage colony forming units (GM-CFU) performed monthly, and peripheral white blood cell count showed an increase of granulocytes not statistically significant and a progressive decrease of GM-CFU that could protect marrow from chemotherapeutic agents or interfere with the myelosuppression of cytotoxic drugs.