A phase I-II study on a gemcitabine-cyclophosphamide-fluorouracil/folinic acid triplet combination in anthracycline- and taxane-refractory breast cancer patients.

PURPOSE: To define the cyclophosphamide (CTX) maximal tolerated dose when combined with fixed doses of gemcitabine, fluorouracil (5-FU) and folinic acid (leucovorin, LFA) in metastatic breast cancer patients pretreated with anthracyclines and taxanes. METHODS: Metastatic breast cancer patients aged < or = 75 years, with ECOG performance status 0-2, were eligible, provided that they had received previous anthracycline- and taxane-based chemotherapy for the advanced disease. Chemotherapy consisted of gemcitabine 1,000 mg/m(2), 5-FU 425 mg/m(2), LFA 100 mg/m(2) and escalating doses of CTX, starting from 500 mg/m(2), on days 1 and 8 every 3 weeks. The dose escalation was stopped if dose-limiting toxicity (DLT) occurred in > 33% of patients of a given cohort. After the definition of DLT, a further escalation with the addition of granulocyte colony-stimulating factor (G-CSF; on days 3-5 and 10-12) was planned. RESULTS: Since March 1999, 69 patients have entered this trial through seven different cohorts. The dose escalation was stopped at the CTX dose of 600 mg/m(2) since 3/6 patients showed DLT. A further dose escalation was attempted in the presence of G-CSF support. A CTX dose of 800 mg/m(2) proved to be safe and was chosen for the phase II. A total of 33 patients were treated at this dose level. The treatment was fairly well tolerated, grade 3-4 neutropenia and thrombocytopenia occurring in 38 and 16% of patients, respectively. No cases of sepsis or bleeding were registered. Four patients required a packed red blood cell transfusion. Severe nonhematologic toxicity was also uncommon, occurring in 10 patients. Three complete and 24 partial responses were recorded for an overall response rate of 38% (95% CI = 26-50). Two complete and 12 partial responses were recorded in the 33 patients treated in the phase II for an overall response rate (ORR) of 42% (95% CI = 25-61). CONCLUSIONS: The gemcitabine-CTX-5-FU/LFA combination is a well-tolerated treatment for poor-prognosis breast cancer patients with previous exposure to anthracyclines and taxanes. With the addition of G-CSF, a cumulative CTX dose of 1,600 mg/m(2) can be safely delivered every 3 weeks. The evidence of an ORR approaching 40% is very promising and justifies further evaluations in this subset of patients.     

Is the Timing of Implantation Affected by Zona Pellucida Micromanipulation?

Purpose: Our purpose was to examine the timing ofimplantation and early embryo development following uterinetransfer of oocytes/embryos previously subjected to zonapellucida micromanipulation. Methods: A total of 68 singleton pregnancies resulting fromIVF and embryo transfer with/without micromanipulation.Patients were divided into four groups according to the typeof micromanipulation technique: assisted hatching, embryobiopsy, intracytoplasmic sperm injection, and nomicromanipulation (control group). Serial serum -hCG levels weremeasured between 10 and 25 days after fertilization andlog-transformed. Linear regression analyses were performedand extrapolated to hCG = 10 mIU/ml (hCG₁₀) to estimatedetectable implantation. The slopes of the regression lineswere used to estimate the rising speed of hCG, an indirectsign of embryo development. Results: There were no significant differences among groupswith respect to hCG₁₀, the slopes or intercepts of theregression lines. Conclusions: Various oocyte/embryo microsurgicalprocedures used in ART involving zona pellucida manipulationdo not appear to affect the timing of implantation or earlyembryo development.     

Methylthiomethyl,a new carboxyl protecting group in peptide synthesis

N^α-protected amino acid methylthiomethyl esters (MTM) were obtained in good yields under mild conditions using the «Bu^tBr/Me₂SO» reagent. Selective removal of the N-protecting group was achieved in HCl/anhydrous ethyl ether and the MTM ester hydrochlorides were successfully used in the synthesis of dipeptides.     

Reversible cerebral perfusion alterations in children with transient mutism after posterior fossa surgery

Mutism is an infrequent and transitory complication observed following posterior fossa surgery. Patients become mute in the immediate postoperative period, with restoration of speech within a few weeks in the absence of additional neurological alterations. The anatomical structures thought to be involved are the connections between the cerebellar dentate nucleus, the ventrolateral nucleus of the contralateral thalamus and the supplementary motor area. In an attempt to understand the pathophysiology of this syndrome, and to depict the perfusion of different brain areas semiquantitatively, in two children who had become mute after posterior fossa surgery we performed a Tc99M-HM-PAO SPECT study during the period of mutism and again when normal speech had returned. In one patient, who had a left cerebellar astrocytoma, the SPECT study showed a marked reduction of cerebral perfusion in the right fronto-parietal region, and in the other, who had a medulloblastoma, a left fronto-temporo-parietal perfusion alteration was observed. When the patients regained normal speech, the follow-up SPECT studies revealed normalization of the cerebral perfusion. This study demonstrates the occurrence of a focal dysfunction of cerebral perfusion in children with cerebellar mutism after posterior fossa surgery. These observations are useful in extending our understanding of the pathophysiology of this postoperative clinical syndrome. Received: 12 September 1997 Revised: 17 November 1997     

Presentation, treatment, and multivariate analysis of risk factors for obstructive and perforative colorectal carcinoma

BACKGROUND: It is known that emergency surgery for colorectal cancer is associated with high morbidity and mortality. The aim of this study was to assess the presentation, treatment, and outcome of patients with complicated colorectal cancer. Risk factors for morbidity and mortality were also evaluated. METHODS: From 1991 to 2002, the medical records of 107 consecutive patients undergoing emergency surgery for obstructing or perforating colorectal carcinoma were retrospectively reviewed. Information regarding patient and tumor characteristics, treatment, and outcome was recorded. Risk factors were assessed by multivariate analysis. RESULTS: Eighty-three patients (78%) had complete obstruction and 24 (22%) had perforation. Overall and major complications occurred in 70% and 34%, respectively. The mortality rate was 15%. Independent risk factors for major morbidity were perioperative blood transfusion and high American Society of Anesthesiologists (ASA) class, whereas those for mortality were older age and high Acute Physiology and Chronic Health Evaluation II (APACHE II) score. CONCLUSIONS: Emergency surgery for complicated colorectal carcinoma carries high rates of morbidity and mortality. To achieve improvements in outcome, intensive treatment after surgery in patients with risk factors is recommended.     

Low calorie commercial sugar is a sensitive marker of glomerular filtration rate

BACKGROUND: Glomerular filtration rate (GFR) in humans and animals might be determined with precision by measuring the clearance of an ideal marker, such as inulin. However, the use of inutest, an inulin analog, is limited by its cost and accessibility. The present study tested whether low calorie commercial sugar (LC sugar) can be used to measure GFR during normal and renal dysfunction. METHODS: Two groups of 6 male Wistar rats weighing 300 to 350 g were included. One group was treated with a daily dose of cyclosporine (CsA) 30 mg/kg subcutaneously for 7 days and the other group was formed by nontreated control rats. In one half of each group, GFR was evaluated by using inutest and in the other half by using LC sugar. GFR was also evaluated by using a wide LC sugar plasma concentration range in an additional group. RESULTS: In nontreated rats, the mean GFR evaluated with LC sugar was 2.2 +/- 0.1 mL/min. This value is equal to that obtained with inutest: 2.3 +/- 0.1 mL/min. CsA administration produced a significant reduction of renal blood flow and renal function. The GFR reduction induced by CsA was similarly determined by both LC sugar and inutest to be at 1.0 +/- 0.2 and 1.1 +/- 0.2 mL/min (P= NS), respectively. In addition, GFR did not change when LC sugar plasma concentration gradually increased. CONCLUSION: Our results show that in both normal and pathophysiologic conditions, LC sugar is a good marker of GFR similar to the gold standard inutest.     

Concordance between qualitative and quantitative cultures in burned patients. Analysis of 2886 cultures

OBJECTIVE: To determine the concordance between superficial cultures (SC) and quantitative cultures (QC) in the diagnosis of wound infection in burn patients. METHOD: Sample: All SC and QC taken from the same patient, site and during the same surgery were analysed. Variables: On the SC, the microorganism (MO) and its amount defined subjectively by the microbiologist was recorded (negative, very low, low, regular and abundant). On the QC, the MO and its amount were expressed as colony forming units per gram of tissue (CFUs/g). Statistics: Kappa index of agreement beyond chance; Wilcoxon and Kruskall-Wallis for continuous variables and chi(2) for categorical variables were used with a p<0.05 indicating statistical significance. RESULTS: One thousand four hundred and forty three pairs of cultures were analyzed. The concordance between SC and QC (Kappa index) was 52%. On the SC, only when the microbiologist subjectively informed "abundant" MOs there was a significant difference (p<0.0001). There were 6.1% of QCs with more than 10(5) CFUs/g and the most frequent MOs isolated were: S. aureus (27.9%), E. coli (11.6%), P. aeruginosa (11.6%), E. faecalis (11.6%) and S. epidermidis (7.0%). CONCLUSIONS: SC has a moderate concordance with the QC showing a low reliability between the two methods. The subjective information given by the microbiology technician in the SC is not precise. A study in which the two methods be compared blindly against the reference standard, in a prospective cohort of patients, it is needed to discriminate which of two methods it is the most accurate one determining sensitivity and specificity.     

Adequacy of laboratory simulation of in-line skater falls

PURPOSE: Currently most laboratory simulation of distal radius fractures and wrist injuries has been with axial limb loading or vertical drop technique. To better assess the contribution of horizontal velocity in momentum in the development of wrist injury and wrist fracture we have compared forces and fracture patterns for fall simulations involving strictly vertical impacts with those that incorporated horizontal momentum in fresh-frozen upper extremities. METHODS: The premise for testing was based on a forward fall onto the palmar surface of an outstretched arm. A 45 degrees-incline impact device was used to model the horizontal and vertical velocity components of a skater fall at a representative speed. Sled mass was 26.2 kg. A 45.5-kg vertical impact system furnished contrasting data and represented prior state-of-the-art technology. Drop heights were adjusted to compensate for discrepancy in sled mass. Measurements from either impact system included vertical and horizontal forces and kinetic energy at impact. Fracture patterns were assessed radiographically. Nine trials were conducted with the incline device and 11 trials were conducted with the vertical impact system. RESULTS: The fracture rate was substantially higher for vertical impacts versus incline impacts (82% vs 33%). The rate of carpal fractures also was higher. Vertical and horizontal forces were similar statistically although slightly greater for vertical impacts. Kinetic energy, however, was 3 times greater for incline impacts than for vertical impacts. These kinetic parameters support the argument that the incline impacts should have resulted in far greater injury. CONCLUSIONS: The data suggest horizontal momentum changes limb loading. We submit that published methods for modeling skater falls have failed to provide a true simulation of the event in question.     

Hand involvement in paraneoplastic syndrome: a case report

Cutaneous paraneoplastic syndromes are skin and mucous membrane changes that are associated with cancer. We report a previously healthy 76-year-old man who developed marked finger and thumb contracture, pain, and hypersensitivity of both hands who was diagnosed subsequently as having gastric carcinoma with colonic metastasis. After the gastrointestinal tumors were resected the finger and thumb contracture lessened and the pain eased. Both the temporal relationship between the changes in the hand and the neoplasm and the improvement after resection suggest a paraneoplastic syndrome.