A Computer Prescribing Order Entry-Clinical Decision Support system designed for neonatal care: results of the 'preselected prescription' concept at the bedside.

WHAT IS KNOWN: The neonatal intensive care units (NICUs) are at the highest risk of drug dose error of all hospital wards. NICUs also have the most complicated prescription modalities. The computerization of the prescription process is currently recommended to decrease the risk of preventable adverse drug effects (pADEs) in NICUs. However, Computer Prescribing Order Entry-Clinical Decision Support (C.P.O.E./C.D.S.) systems have been poorly studied in NICUs, and their technical compatibility with neonatal specificities has been limited. OBJECTIVES: We set up a performance study of the preselected prescription of drugs for neonates, which limited the role of the prescriber to choosing the drugs and their indications. METHODS: A single 29 bed neonatal ward used this neonatal C.P.O.E./C.D.S. system for all prescriptions of all hospitalized newborns over an 18-month period. The preselected prescription of drugs was based on the indication, gestational age, body weight and post-natal age. The therapeutic protocols were provided by a formulary reference (330 drugs) that had been specifically designed for newborns. The preselected prescription also gave complete information about preparation and administration of drugs by nurses. The prescriber was allowed to modify the preselected prescription but alarms provided warning when the prescription was outside the recommended range. The main clinical characteristics and all items of each line of prescription were stored in a data warehouse, thus enabling this study to take place. RESULTS: Seven hundred and sixty successive newborns (from 24 to 42 weeks' gestation) were prescribed 52 392 lines of prescription corresponding to 65 drugs; About 30·4% of neonates had at least one out of licensed prescription; A prescription out of the recommended range for daily dose was recorded for 1·0% of all drug prescriptions. WHAT IS NEW?: The C.P.O.E./C.D.S. systems can currently provide a complete preselected prescription in NICUs according to dose rules, which are specific to newborns and also comply with local specificities (therapeutic protocols and formulation of drugs). The role of the prescriber is limited to the choice of drugs and their indications. The prescriber still retains the possibility of modifying each item of the prescription, with all other prescription items being calculated by the C.P.O.E. system. In these conditions, the prescribers rarely modified the preselected prescription and the rate of out of range prescription was low. A multicentric study is required to confirm and extend these observations. CONCLUSIONS: This study showed the feasibility of preselected prescription in NICUs and a low rate of out of range prescriptions. The preselected prescription could play a key role in lowering the dose error rate in NICUs.

Current practices used for the prevention of central venous catheter-associated infection in hematopoietic stem cell transplantation recipients: a survey from the Infectious Diseases Working Party and Nurses' Group of EBMT.

BACKGROUND: Central line-associated bloodstream infection (CLABSI) is one of the most common infectious complications after hematopoietic stem cell transplantation. To prevent this complication, international guidelines recommend the implementation of the CLABSI 'prevention bundle' consisting of hand hygiene, full barrier precautions, cleaning the insertion site with chlorhexidine, avoiding femoral sites for insertion, and removing unnecessary catheters. The aim of this survey was to analyze to what extent European Group for Blood and Marrow Transplantation (EBMT) centers have included the CLABSI prevention bundle in practice. METHODS: A questionnaire used for data collection was sent to the 545 EBMT centers worldwide, 103 of which responded. RESULTS: All 5 components of the CLABSI prevention bundle were recorded in 28% of the centers' standard operating procedures (SOP), and 21% of the centers answered that they used all of the bundle components in clinical practice. The most common recommendation absent from the SOP was specification of all the components of full barrier precautions (43% of the centers did not include at least 1 component). Skin disinfection with chlorhexidine before catheter insertion was reported by 66% centers. CLABSI rates were monitored in 21% of centers. CONCLUSIONS: Although most of the centers lacked 1 or more of the CLABSI prevention bundle components in their SOP, improvements could easily be made by updating the centers' SOP. The first important step is introduction of CLABSI rate monitoring in this high-risk patient population.

Original technique for preoperative preparation of patients and intraoperative localization of parathyroid adenomas.

Surgical approach of single parathyroid adenoma treatment is turning to a less invasive surgery, allowing us to obtain better aesthetic results, reduction of duration of surgical operation, reduction of post-operative morbidity and hospital stay. Tc99m-sestaMIBI scintigraphy is mainly performed for preoperative localization of parathyroid adenomas. Our technique is instead based on the possibility to inhibit the interference of Tc99m-sestaMIBI uptake of the thyroid gland by means of the administration of Lugol's solution. Indeed, to confirm the identification and removal of the hyperfunctional parathyroid, it is accepted as adequate an ex vivo radioactivity count of the adenoma 20% or 40% greater than the value of the post-excisional background radioactivity, in association or not with intraoperative measurement of PTH. This method allows us to perform surgery with no timetable restriction, and to clearly distinguish the radioactivity of parathyroid adenoma from that of the surrounding tissues and thyroid gland.

Frequency of dosage prescribing medication errors associated with manual prescriptions for very preterm infants.

WHAT IS KNOWN AND OBJECTIVE: The risk of dosage Prescription Medication Error (PME) among manually written prescriptions within 'mixed' prescribing system (computerized physician order entry (CPOE) + manual prescriptions) has not been previously assessed in neonatology. This study aimed to evaluate the rate of dosage PME related to manual prescriptions in the high-risk population of very preterm infants (GA < 33 weeks) in a mixed prescription system. METHODS: The study was based on a retrospective review of a random sample of manual daily prescriptions in two neonatal intensive care units (NICU) A and B, located in different French University hospitals (Dijon and La Reunion island). Daily prescription was defined as the set of all drugs manually prescribed on a single day for one patient. Dosage error was defined as a deviation of at least ±10% from the weight-appropriate recommended dose. RESULTS AND DISCUSSION: The analyses were based on the assessment of 676 manually prescribed drugs from NICU A (58 different drugs from 93 newborns and 240 daily prescriptions) and 354 manually prescribed drugs from NICU B (73 different drugs from 131 newborns and 241 daily prescriptions). The dosage error rate per 100 manually prescribed drugs was similar in both NICU: 3·8% (95% CI: 2·5-5·6%) in NICU A and 3·1% (95% CI: 1·6-5·5%) in NICU B (P = 0·54). Among all the 37 identified dosage errors, the over-dosing was almost as frequent as the under-dosing (17 and 20 errors, respectively). Potentially severe dosage errors occurred in a total of seven drug prescriptions. None of the dosage PME was recorded in the corresponding medical files and information on clinical outcome was not sufficient to identify clinical conditions related to dosage PME. Overall, 46·8% of manually prescribed drugs were off label or unlicensed, with no significant differences between prescriptions with or without dosage error. The risk of a dosage PME increased significantly if the drug was included in the CPOE system but was manually prescribed (OR = 3·3; 95% CI: 1·6-7·0, P < 0·001). WHAT IS NEW AND CONCLUSION: The presence of dosage PME in the manual prescriptions written within mixed prescription systems suggests that manual prescriptions should be totally avoided in neonatal units.

Unknown primary tumors.

An unknown primary tumor (UPT) is defined by the presence of a metastatic cancer without a known primary site of origin despite a standardized diagnostic workup. Clinically, UPTs show rapid progression and early dissemination, with signs and symptoms related to the metastatic site. The molecular bases of their biology remain largely unknown, with no evidence as to whether they represent a distinct biological entity. Immunohistochemistry remain the best diagnostic tool in term of cost-effectiveness, but the time-consuming "algorithmic process" it relies on has led to the application of new molecular techniques for the identification of the primary site of UPTs. For example, several microarray or miRNA classifications of UPTs have been used, with an accuracy in the prediction of the primary site as high as 90%. It should be noted that validating a prediction of tissue origin is challenging in these patients, since most of them will never have a primary site identified. Moreover, prospective studies to determine whether selection of treatment options based on such profiling methods actually improves patient outcome are still missing. In the last few years functional imaging (i.e. FDG-PET/CT) has gained a main role in the detection of the site of origin of UPTs and is currently recommended by the European Association of Nuclear Medicine. However, despite recent refinements in the diagnostic workup, the site of origin of UPT often remains elusive. As a consequence, treatment of patients with UPT is still empirical and inadequate.

Sex moderates circadian chemotherapy effects on survival of patients with metastatic colorectal cancer: a meta-analysis.

BACKGROUND: Molecular circadian clocks can modify cancer chemotherapy effects, with a possible moderation according to sex differences. We investigated whether sex determine the optimal delivery schedule of chemotherapy for metastatic colorectal cancer. PATIENTS AND METHODS: A meta-analysis was performed using individual data from three international Phase III trials comparing 5-fluorouracil, leucovorin and oxaliplatin administered in chronomodulated (chronoFLO) or conventional (CONV) infusions. The data from 345 females and 497 males were updated at 9 years. The main end point was survival. RESULTS: Overall survival was improved in males on chronoFLO when compared with CONV (P = 0.009), with respective median values of 20.8 (95% CL, 18.7 to 22.9) and 17.5 months (16.1 to 18.8). Conversely, median survival was 16.6 months (13.9 to 19.3) on chronoFLO and 18.4 months (16.6 to 20.2) on CONV in females (P = 0.012). The sex versus schedule interaction was a strong predictive factor of optimal treatment schedule, with a hazard ratio of 1.59 (1.30 to 1.75) for overall survival (P = 0.002) in multivariate analysis. CONCLUSIONS: Males lived significantly longer on chronomodulated chemotherapy rather than on conventional chemotherapy. The current chronoFLO schedule deserves prospective assessment as a safe and more effective first-line treatment option than conventional delivery for male patients.

Prevalence and risk factors for gonococcal infection in Reunion Island.

OBJECTIVE: To determine the prevalence and risk factors for gonococcal infection, and the resistance profile of Neisseria gonorrhoeae (NG) in Reunion Island. PATIENTS AND METHODS: All patients who visited the four sexually transmitted infection (STI) clinics of Reunion Island between January 2017 and December 2018 were screened by multiplex polymerase chain reaction. Data on patient characteristics were collected using a self-administered questionnaire (reason for screening, marital status, risk-taking behaviors, place of birth, employment status, type of health care coverage, sexual orientation, number of sexual partners, occurrence of extra-marital relationships, history of STIs, and symptomatology. Precarity was defined as being unemployed and/or receiving universal health insurance). RESULTS: The prevalence of NG (n=4289) in the screened population was 2.8% (95% CI [2.3-3.3]). Minors were especially at-risk (4.4% (95% CI [2.6-7])) and especially girls (5.6% (95% CI [3.2-8.9])). The prevalence observed in the homosexual population was 4.0% [2.6-5.9]. Gonococcal infection was asymptomatic in 56 (69%) patients. For all infection sites, the main risk factors were male minors (P=0.019), individuals living in conditions of precarity (P=0.023), individuals co-infected with chlamydia (P<0.001) or syphilis (P<0.001), and individuals of foreign origin (P=0.006). No NG strain was resistant to ceftriaxone. Strains were resistant to penicillin G, ciprofloxacin, and azithromycin in 22% (20/91), 38% (35/91), and 1% (1/91) of cases, respectively. CONCLUSION: The prevalence of NG in patients visiting STI clinics in Reunion Island is particularly high among minors. Prevention programs targeting this population should be reinforced and screening should be facilitated in school settings.

Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans.

Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.

An immunohistochemically positive E-cadherin status is not always predictive for a good prognosis in human breast cancer.

BACKGROUND: in primary breast cancers dichotomic classification of E-cadherin expression, according to an arbitrary cutoff, may be inadequate and lead to loss of prognostic significance or contrasting prognostic indications. We aimed to assess the prognostic value of high and low E-cadherin levels in a consecutive case series (204 cases) of unilateral node-negative non-lobular breast cancer patients with a 8-year median follow-up and that did not receive any adjuvant therapy after surgery. METHODS: expression of E-cadherin was investigated by immunohistochemistry and assessed according to conventional score (0, 1+, 2+, 3+). Multiple correspondence analysis was used to visualise associations of both categorical and continuous variables. The impact of E-cadherin expression on patients outcome was evaluated in terms of event-free survival curves by the Kaplan-Meier method and proportional hazard Cox model. RESULTS: respect to intermediate E-cadherin expression values (2+), high (3+) or low (0 to 1+) E-cadherin expression levels had a negative prognostic impact. In fact, both patients with a low-to-nil (score 0 to 1+) expression level of E-cadherin and patients with a high E-cadherin expression level (score 3+) demonstrated an increased risk of failure (respectively, hazard ratio (HR)=1.71, confidence interval (CI)=0.72-4.06 and HR=4.22, CI=1.406-12.66) and an interesting association with young age. CONCLUSIONS: the findings support the evidence that high expression values of E-cadherin are not predictive for a good prognosis and may help to explain conflicting evidence on the prognostic impact of E-cadherin in breast cancer when assessed on dichotomic basis.

Chemoprophylaxis in gastrointestinal tumors.

Chemoprevention of gastrointestinal tumors uses natural or synthetic agents to arrest, retard or reverse the carcinogenesis process. The prospect of prevention is clearly appealing, especially for colorectal cancer (CRC), that represents the second most common cause of cancer-related death in the Western world. Aspirin is the best studied chemopreventive agent for CRC, with randomized trials demonstrating its efficacy in reducing recurrence of colorectal adenomas in higher risk patients. Optimal chemoprevention requires long-term use and high dose of aspirin that may increase the risk of gastrointestinal bleeding. Other nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors also reduce the incidence of colonic adenomas, but they are associated with gastrointestinal harms and important cardiovascular events, respectively. Furthermore, cumulative epidemiological and observational data suggest the potential role of hormones as a chemoprotective agent for CRC. The usefulness of folic acid, calcium, and vitamin D awaits further evaluation. Interestingly, combining different agents may maximize effectiveness while limiting drug toxicity. Although many agents have shown positive results in the field of chemoprevention, it cannot yet be accepted as standard medical practice for CRC. In the present review we discuss the most promising agents in CRC chemoprevention, together with their potential mechanisms of action in tumor inhibition.

Risk factors associated with severe perineal tears: A five-year study.

OBJECTIVE: Our aim was to describe risk factors associated with 34DPT in operative and non-operative vaginal deliveries, over a five-year period. STUDY DESIGN: This was a retrospective cohort study including 39,227 vaginal deliveries from 2013 to 2017 in a single French University Hospital. Annual characteristics of the analyzed population were recorded. Univariate logistic regression was used to evaluate the association between these characteristics and 34DPT. Multivariate analysis was used to identify combinations of risk factors associated with instrumental delivery. RESULTS: The rate of perineal tears was constantly rising but rate of 34DPT was stable, ranging between 0.8 and 1.4% over the study period. Cesarean section rate was stable between 18.8% and 19.6%. Rate of diabetes, preeclampsia and obesity (BMI < 40) was increasing and episiotomy rate decreasing (from 19.8% to 11.8%). Operative deliveries rate remained stable between 11 and 12.8%. Multivariate regression showed that gestational age over 39 weeks (aOR 1.18, 95% CI [1.02; 1.35]), birth weight over 3500 g (aOR 1.62, 95% CI [1.05; 2.49]) were associated with 34DPT in patients without operative vaginal deliveries but not episiotomy. Gestational age (aOR 1.71, 95% CI [1.18; 2.47]), episiotomy (aOR 0.55, 95% CI [0.38; 0.79]) and diabetes (aOR 1.73, 95% CI [1.15; 2.61]) were associated with 34DPT among patients with operative vaginal deliveries. CONCLUSION: In a tertiary medical center model with low cesarean section rate, factors associated with 34DPT were different among patients with or without operative vaginal delivery. The question of the protective effect of mediolateral episiotomy against 34DPT in case of operative delivery deserves further investigations.

Discussion about switch strategy in the adjuvant hormonal therapy of breast cancer: psychological aspects of physician-patient communication.

BACKGROUND: A survey of oncologists was conducted in Italy to evaluate the potential problems of physician-patient discussion about hormonal switch in the adjuvant therapy of breast cancer. MATERIALS AND METHODS: A questionnaire, including both closed and open-ended questions, was administered to 70 oncologists. Fifty-one of them returned completely filled questionnaires. RESULTS: Forty-seven percent of the physicians reported difficulties in proposing the hormonal switch, and 60% stated that they found it difficult to make the therapeutic change acceptable to patients. The oncologist's barriers to propose the switch were related mostly to scientific and economic issues, such as the lack of certain advantages of aromatase inhibitors over tamoxifen (28%), their costs (14%) and their side-effects (34%). On the other hand, according to physicians, the patient's barriers to accept the therapeutic change were mainly due to psychological-relational factors, in particular the anxiety produced by the change (40%) and the bad patient-physician communication experienced in the past (26%). CONCLUSIONS: Patient-physician communication difficulties about switch strategy in the adjuvant hormonal treatment of breast cancer are, at least in part, related to psychological and relational factors. It is likely that training programs, improving doctor's communication skills, can overcome these problems.

EBMT prospective observational study on allogeneic hematopoietic stem cell transplantation in T-prolymphocytic leukemia (T-PLL).

Preliminary data suggest that allogeneic stem cell transplantation (allo-SCT) may be effective in T-prolymphocytic leukemia (T-PLL). The purpose of the present observational study was to assess the outcome of allo-SCT in patients aged 65 years or younger with a centrally confirmed diagnosis of T-PLL. Patients were consecutively registered with the EBMT at the time of transplantation and followed by routine EBMT monitoring but with an extended dataset. Between 2007 and 2012, 37 evaluable patients (median age 56 years) were accrued. Pre-treatment contained alemtuzumab in 95% of patients. Sixty-two percent were in complete remission (CR) at the time of allo-SCT. Conditioning contained total body irradiation with 6 Gy or more (TBI6) in 30% of patients. With a median follow-up of 50 months, the 4-year non-relapse mortality, relapse incidence, progression-free (PFS) and overall survival were 32, 38, 30 and 42%, respectively. By univariate analysis, TBI6 in the conditioning was the only significant predictor for a low relapse risk, and an interval between diagnosis and allo-SCT of more than 12 months was associated with a lower NRM. This study confirms for the first time prospectively that allo-SCT can provide long-term disease control in a sizable albeit limited proportion of patients with T-PLL.

Sick leave for follow-up control in thyroid cancer patients: comparison between stimulation with Thyrogen and thyroid hormone withdrawal.

INTRODUCTION: The clinical benefits of recombinant human thyroid-stimulating hormone (rhTSH; Thyrogen) are well established as an alternative stimulation procedure to thyroid hormone withdrawal in the diagnostic follow-up of thyroid cancer patients. By avoiding periods of hypothyroidism, patients do not suffer from a decreased quality of life and keep their ability to work. This study compared the frequency, the duration and the cost of sick leave for follow-up control between rhTSH and withdrawal. METHODS: The study population consisted of patients with thyroid carcinoma first treated by thyroidectomy and radioiodine ablation. Patients were recruited at their control visit between October 2004 and May 2006 in three hospitals, both prospectively and retrospectively. Collection data consisted of patient information, job characteristics and duration of sick leave during the month before and the month after control. The valuation of sick leave used the friction cost method. RESULTS: Among the 306 patients included, 292 (95%) completed the entire questionnaire. The mean age was 46.7 years. Among the 194 active patients, patients treated with rhTSH, when compared with patients treated by withdrawal, were less likely to require sick leave (11 vs 33%; P=0.001). The mean duration of sick leave was shorter (3.1 vs 11.2 days; P=0.002) and indirect costs due to absenteeism accounted for 454 Euro +/- 1673 vs 1537 Euro +/- 2899 for withdrawal stimulation. CONCLUSION: For active patients, rhTSH treatment reduced the length and the cost of sick leave by 8.1 days and 1083 Euro per control respectively, when compared with withdrawal treatment.

Novel P53 mutations detected by FAMA in colorectal cancers.

BACKGROUND: The aim of the study was to identify p53 gene mutations by FAMA (fluorescence-assisted mismatch analysis) in colorectal cancers. PATIENTS AND METHODS: Analytical scanning of the p53 gene (exons 5-9) was performed in colon cancer samples from 44 consecutive patients by FAMA. FAMA is a semiautomatic scanning approach based on the chemical cleavage of the mismatch in fluorescently labeled heteroduplex DNA, obtained from the combination of a normal and a mutated allele. FAMA has already shown optimal levels of diagnostic accuracy and sensitivity in detecting gene mutations (nucleotide substitutions, insertions/deletions) both at the germline and somatic level. The peculiar feature of FAMA is its ability to detect and localize mutations, by a redundant pattern of signals due to fluorescent DNA fragments generated by chemical cleavage. Moreover, previous data have demonstrated that normal contaminating DNA from stromal cells in the sample does not affect the sensitivity of the procedure, leading to the identification of the mutation even when the ratio mutant/normal allele is 10%. RESULTS: Eighteen mutations (12 missense, one nonsense, two deletions, three nucleotide substitutions at the level of the splice-junctions) and two polymorphisms were detected by FAMA in 17 patients (39%) and then confirmed by automated sequence analysis. Six of 18 mutations (33%) were not previously reported for colon cancer samples and two of 18 lesions (11%) were identified as novel p53 mutations. CONCLUSIONS: Analytical scanning of the p53 gene by FAMA in DNA from colon cancer samples provides a sensitive, accurate and specific diagnostic procedure for routine clinical application.

Patterns of K-ras mutation in colorectal carcinomas from Iran and Italy (a Gruppo Oncologico dell'Italia Meridionale study): influence of microsatellite instability status and country of origin.

BACKGROUND: K-ras mutations are a key step in colorectal cancer progression. Such mutations have been widely studied in case series from Western countries but there are few data on the rate and spectrum of mutations in tumors from countries where the epidemiological features of the disease are different. PATIENTS AND METHODS: Tumor samples from 182 Iranian colorectal cancer patients (170 sporadic cases and 12 HNPCC cases) were screened for K-ras mutations at codons 12, 13 and 61 by sequencing analysis. The cases were also characterized for microsatellite instability at mononucleotide repeats by PCR and fragment analysis, and classified according to microsatellite instability status. The frequency and the spectrum of K-ras mutations were compared with those observed in a series of colorectal cancer patients from Italy. RESULTS: K-ras mutations were observed in 68/182 (37.4%) cases. Mutation frequencies were similar in HNPCC-associated, sporadic MSI-H and sporadic microsatellite-stable (MSS) tumors. However, the G13D substitution was more frequent in HNPCC (3/4, 75%) and sporadic MSI-H (7/11, 63.6%) tumors compared to sporadic MSS tumors (11/53, 20.4%) (P <0.01). Comparison of mutations in the two series from Iran and Italy showed a significantly higher frequency of G13D among Italian patients. CONCLUSIONS: While the frequency of K-ras mutations could be similar, the mutational spectrum could be differentially influenced by genetic and environmental factors.

Increased tolerability of bimonthly 12-hour timed flat infusion 5-fluorouracil/irinotecan regimen in advanced colorectal cancer: A dose-finding study.

A dose-finding study was designed to determine the maximum tolerated dose (MTD) of a bimonthly 12-h (10:00 p.m to 10:00 a.m), timed flat infusion (TFI) of 5-fluorouracil (5-FU) plus irinotecan (CPT-11), without leucovorin (LV), for metastatic colorectal carcinoma (CRC). A total of 33 patients were treated. Seven dose levels included a fixed CPT-11 dose of 180 mg/m2 on days 1 and 15 (d(1,15)) and escalating doses of 5-FU 600-1200 mg/m2 on days 1-4 and 15-18 (d(1-4,15-18)). Dose-limiting toxicities (DLTs) were: grade 3-4 non-hematologic, grade 4 hematologic and any toxicity causing a more than a 2-week delay in treatment. The MTD was reached at the seventh dose level. DLTs were observed in 5/8 patients (63%): G3 diarrhea, 2 patients, associated with G3 mucositis in one instance; G4 neutropenia, 2 patients, associated with severe asthenia in 1 patient; G3 hand-foot syndrome, 1 patient. The recommended doses (RDs) were established at the sixth dose level: 5-FU, 1100 mg/m2/d(1-4,15-18); CPT-11 180 mg/m2/d(1,15) [5-FU and CPT-11 dose intensity (DI), 2200 and 90 mg/m2 per week (w), respectively]. At the recommended dose, the DLTs in 38 cycles were: mucositis, 2 cycles (5%); afebrile G4 neutropenia and hand-foot syndrome, 1 cycle (3%). In 24 assessable patients, the overall response rate was 37.5%. The present CPT-11/5-FU schedule is highly tolerable in an outpatient setting using the highest recommended 5-FU dose effective in advanced CRC.

Aquaporin-2 excretion and renal function during the 1st week of life in preterm newborn infants.

In many preterm infants, a characteristic pattern of fluid and electrolyte homeostasis occurs during the 1st week of life, consisting of three phases: prediuretic, diuretic, and postdiuretic. In this study, we evaluated the possible role of aquaporin-2 (AQP2) in renal concentrating ability and correlated it with other markers of the renal function in healthy preterm infants. Daily urine and spot blood samples were collected from 9 healthy preterm (32 +/- 1 weeks) infants at postnatal ages 1, 3, and 7 days. Urine and serum osmolality, creatinine, electrolytes, and AQP2 excretion were measured. All infants showed a significant (about 7%) weight loss on day 3 associated with a more than threefold increase in urine output without a significant change in fluid intake (diuretic phase). The creatinine clearance increased on day 3, indicating an increase in glomerular filtration rate. Interestingly, on day 3, the level of total excreted AQP2 (pmol/h) was significantly higher when compared to day 1 and day 7, and the same tendency was observed for urine osmolality. To conclude, the observed increase in urine osmolality and creatinine clearance during the diuretic phase, paralleled by an increase in total AQP2 excretion, suggests that AQP2 can contribute to the urinary concentrating ability early in postnatal life.

[Hairy cell leukemia: prognosis and treatment]. / La tricoleucemia: prognosi e terapia.

AIMS: To analyze clinical and laboratory features at presentation in correlation to treatment response and overall survival; evaluation of different treatment approaches. METHODS: The data of 151 consecutive HCL patients observed between 1982 and 2005 were retrospectively analyzed. RESULTS: The following data at presentation were analyzed and compared to response, DFS, PFS and OS: Hb < 10 g/dl (observed in 27% of patients); Plt < 100,000/microl (72%); WBC > 10,000/microl (15%); Splenomegaly (75%); Bone marrow involvement > 70% (27%). At univariate analysis only WBC > 10,000/microl resulted significantly correlated to reduced PFS. 88 Pts received as first line treatment alpha2-interferon (IFN) alone, 49 purine analogues (PA) alone or in combination with IFN, 5 were treated with splenectomy. Among IFN treated patients CR, PR and SD were obtained in 21.6%, 73.8%, 4.5% respectively of the patients; while among PA treated patients in: 26.5%, 71.4%, 2.0% respectively. DFS was significantly prolonged in patients treated with PA with respect to IFN. No significant difference in OS was observed. Median PFS was 27.6 months, median OS is projected at 238 months after a median follow up of 131 months. CONCLUSIONS: Among the routine clinical and hematochemical baseline features only the presence of WBC > 10,000/microl was correlated to a lower PFS. First line treatment with purine analogues is correlated to prolonged PFS and DFS with respect to IFN; nevertheless no difference is observed in OS.

Detection of antigens recognized by a novel monoclonal antibody in tissue and serum from patients with breast cancer.

Monoclonal antibodies were produced in mice immunized with proteins released into tissue culture fluid of human breast cancer cells maintained in vitro. One monoclonal antibody (SP-2) identified a Mr 90,000 antigen which appears to be a proteolipid. In immunoperoxidase assays, SP-2 reacted with 81 of 90 specimens of human breast cancer. It also reacted with 12 of 23 cancers of nonbreast origin but was unreactive with all normal tissues tested. The Mr 90,000 antigen, purified by immunoaffinity chromatography using SP-2, was used in an indirect binding inhibition assay for the detection of antigen in human serum. With this assay, 35 of 69 patients with breast cancer and 11 of 37 patients with benign breast lesions showed serum antigen levels above 6 units/ml. Patients with nonbreast cancers also demonstrated elevated levels of antigen in 32% of cases. The SP-2 defined Mr 90,000 antigen appeared to be distinct from carcinoembryonic antigen and other monoclonal antibody-defined breast cancer antigens of similar molecular weight. SP-2 may prove useful as a serum and/or tissue marker in breast pathology.